Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead

The knowledge that the body possesses natural defenses to combat cancer existed long before the modern period,with multiple anecdotal reports of tumors miraculously disappearing,sometimes spontaneously or after a febrile or infectious episode.Spontaneous tumor regression of untreated malignant tumors is currently a well-accepted albeit rare phenomenon,and it is recognized that immunosuppression is associated with a higher cancer risk.The treatment of bladder carcinoma by intravesical administration of live attenuated Bacillus Calmette-Guérin bacteria was shown to be very effective in 1976 and is now standard treatment.Effective immunity against cancer involves complex interactions between the tumor,the host,and the environment.Cancer immunotherapy uses various strategies to augment tumor immunity and represents a paradigm shift in treating cancer,since attention has become more focused on the“biologic passport”of the individual tumor rather than the site of origin of the tumor.The different types of cancer immunotherapies discussed here include biologic modifiers,such as cytokines and vaccines,adoptive cell therapies,oncolytic viruses,and antibodies against immune checkpoint inhibitors,such as the co-inhibitory T-cell receptor PD-1 and one of its ligands,programmed death-ligand 1.

Targeting the JAK/STAT pathway in solid tumors

Aberrant activation of signal transducer and activator of transcription(STAT)proteins is associated with the development and progression of solid tumors.However,as transcription factors,these proteins are difficult to target directly.In this review,we summarize the role of targeting Janus kinases(JAKs),upstream activators of STATs,as a strategy for decreasing STAT activation in solid tumors.Preclinical studies in solid tumor cell line models show that JAK inhibitors decrease STAT activation,cell proliferation,and cell survival;in in vivo models,they also inhibit tumor growth.JAK inhibitors,particularly the JAK1/2 inhibitor ruxolitinib,sensitize cell lines and murine models to chemotherapy,immunotherapy,and oncolytic viral therapy.Ten JAK inhibitors have been or are actively being tested in clinical trials as monotherapy or in combination with other agents in patients with solid tumors;two of these inhibitors are already Food and Drug Administration(FDA)approved for the treatment of myeloproliferative disorders and rheumatoid arthritis,making them attractive agents for use in patients with solid tumors as they are known to be well-tolerated.Four JAK inhibitors(two of which are FDA approved for other indications)have exhibited promising anti-cancer effects in preclinical studies;however,clinical studies specifically assessing their activity against the JAK/STAT pathway in solid tumors have not yet been conducted.In summary,JAK inhibition is a viable option for targeting the JAK/STAT pathway in solid tumors and merits further testing in clinical trials.

Photodynamic therapy in cancer treatment - an update review

Cancer remains a worldwide health problem, being the disease with the highest impact on global health. Even with all the recent technological improvements, recurrence and metastasis still are the main cause of death. Since photodynamic therapy (PDT) does not compromise other treatment options and presents reduced long-term morbidity when compared with chemotherapy or radiotherapy, it appears as a promising alternative treatment for controlling malignant diseases. In this review, we set out to perform a broad up-date on PDT in cancer research and treatment, discussing how this approach has been applied and what it could add to breast cancer therapy. We covered topics going from the photochemical mechanisms involved, the different cell death mechanisms being triggered by a myriad of photosensitizers up to the more recent-on-going clinical trials.

Autophagy in breast cancer metastatic dormancy:tumor suppressing or tumor promoting functions?

Breast cancer is the second leading cause of cancer-associated death in women in the United States, with more than 90% of those deaths attributed to metastasis. Breast cancer metastasis is incurable and possesses few treatment options and a poor overall prognosis due in part to confounding metastatic attributes, particularly the acquisition of dormancy-associated phenotypes. Dormant disseminated tumor cells can persist for years-to-decades before recurring as highly aggressive, secondary lesions. Dormancy-associated phenotypes are exhibited by breast cancer stem cells (BCSCs), which undergo tumor initiation and unlimited self-renewal. In addition to their specialized abilities to circumvent chemotherapeutic insults, BCSCs also upregulate autophagy during metastatic dormancy as a means to survive in nutrient poor conditions and environmental stress. As such, therapeutic targeting of autophagy is actively being pursued as an attractive strategy to alleviate metastatic disease and the recurrence of dormant BCSCs. Here we review the molecular and cellular features of autophagy, as well as its paradoxical role in both suppressing and promoting mammary tumor development and metastatic progression. Finally, we highlight the clinical challenges associated with therapeutic targeting of autophagy in metastatic breast cancers.

NSAID celecoxib: a potent mitochondrial pro-oxidant cytotoxic agent sensitizing metastatic cancers and cancer stem cells to chemotherapy

Intermittent hypoxia within tumor microenvironments causes pro-oxidative stress impairing oxidative phos-phorylation(OxPhos)and increases mitochondrial production of reactive oxygen species(ROS).In primary tu-mors this provokes metabolic reprogramming of both tumor cells and cancer stem cells and emergence of highly metastatic cancer cells.Tumor reprogramming is initiated by activating nuclear respiratory factors and hypoxia-inducible factors in response to changes in oxygen and ROS levels.Hence,hypoxia-induced pro-oxidative stress drives invasion and metastasis.However,it is also the Achilles’heel of metastatic cancer cells because pro-oxi-dative agents further overload the mitochondria and intracellular milieu with excessive ROS to trigger apoptosis,whereas antioxidant agents promote their survival and tumor progression.Herein lies the metastatic tumor cell sensitivity to non-steroidal anti-inflammatory drugs(NSAIDs)and we and others have shown that the NSAID celecoxib exerts powerful pro-oxidative anticancer effects by directly targeting mitochondria to increase ROS production and trigger cancer cell death,including metastatic cancer cells and cancer stem cells.This review highlights the considerable benefits from appropriate NSAID use in humans against post-diagnosis metastatic tumors and the need to further develop their use as adjuvant therapy for advanced stage metastatic disease where they are already showing significantly improved clinical outcomes.

Extracellular RNAs as potential biomarkers for cancer

The discovery that all cells secrete extracellular vesicles(EVs)to shuttle proteins and nucleic acids to recipient cells suggested they play an important role in intercellular communication.EVs are widely distributed in many body fluids,including blood,cerebrospinal fluid,urine and saliva.Exosomes are nano-sized EVs of endosomal origin that regulate many pathophysiological processes including immune responses,inflammation,tumour growth,and infection.Healthy individuals release exosomes with a cargo of different RNA,DNA,and protein contents into the circulation,which can be measured non-invasively as biomarkers of healthy and diseased states.Cancer-derived exosomes carry a unique set of DNA,RNA,protein and lipid reflecting the stage of tumour progression,and may serve as diagnostic and prognostic biomarkers for various cancers.However,many gaps in knowledge and technical challenges in EVs and extracellular RNA(exRNA)biology,such as mechanisms of EV biogenesis and uptake,exRNA cargo selection,and exRNA detection remain.The NIH Common Fund-supported exRNA Communication Consortium was launched in 2013 to address major scientific challenges in this field.This review focuses on scientific highlights in biomarker discovery of exosome-based exRNA in cancer and its possible clinical application as cancer biomarkers.

Cancer immunity and therapy using hyperthermia with immunotherapy, radiotherapy, chemotherapy, and surgery

Hyperthermia is a type of medical modality for cancer treatment using the biological effect of artificially induced heat.Even though the intrinsic effects of elevated body temperature in cancer tissues are poorly understood,increasing the temperature of the body has been recognized as a popular therapeutic method for tumorous lesions as well as infectious diseases since ancient times.Recently accumulated evidence has shown that hyperthermia amplifies immune responses in the body against cancer while decreasing the immune suppression and immune escape of cancer.It also shows that hyperthermia inhibits the repair of damaged cancer cells after chemotherapy or radiotherapy.These perceptions indicate that hyperthermia has potential for cancer therapy in conjunction with immunotherapy,chemotherapy,radiotherapy,and surgery.Paradoxically,the anticancer effect of hyperthermia alone has not yet been adequately exploited because deep heating techniques and devices to aggregate heat effects only in cancer tissues are difficult in practical terms.This review article focuses on the current understanding concerning cancer immunity and involvement of hyperthermia and the innate and adoptive immune system.The potential for combination therapy with hyperthermia and chemotherapy,radiotherapy,and surgery is also discussed.

hnRNP E1 at the crossroads of translational regulation of epithelial-mesenchymal transition

The epithelial-mesenchymal transition(EMT),in which cells undergo a switch from a polarized,epithelial phenotype to a highly motile fibroblastic or mesenchymal phenotype is fundamental during embryonic development and can be reactivated in a variety of diseases including cancer.Spatio-temporally-regulated mechanisms are constantly orchestrated to allow cells to adapt to their constantly changing environments when disseminating to distant organs.Although numerous transcriptional regulatory factors are currently well-characterized,the post-transcriptional control of EMT requires continued investigation.The hnRNP E1 protein displays a major role in the control of tumor cell plasticity by regulating the translatome through multiple non-redundant mechanisms,and this role is exemplified when E1 is absent.hnRNP E1 binding to RNA molecules leads to direct or indirect translational regulation of specific sets of proteins:(1)hnRNP E1 binding to specific targets has a direct role in translation by preventing elongation of translation;(2)hnRNP E1-dependent alternative splicing can prevent the generation of a competing long non-coding RNA that acts as a decoy for microRNAs(miRNAs)involved in translational inhibition of EMT master regulators;(3)hnRNP E1 binding to the 3'untranslated region of transcripts can also positively regulate the stability of certain mRNAs to improve their translation.Globally,hnRNP E1 appears to control proteome reprogramming during cell plasticity,either by direct or indirect regulation of protein translation.

Metabolic alterations and the potential for targeting metabolic pathways in the treatment of multiple myeloma

Metabolism is defined as the collection of complex biochemical processes that living cells use to generate energy and maintain their growth and survival. Metabolism encompasses the synthesis and breakdown of glucose, fatty acids, and amino acids;the generation of energy (ATP);and oxidative phosphorylation. In cancer cells, metabolism can be commandeered to promote tumor growth and cellular proliferation. These alterations in metabolism have emerged as an additional hallmark of various cancers. In this review we focus on metabolic alterations in multiple myeloma (MM) - a malignancy of plasma cells - including derangements in glycolysis, gluconeogenesis, the tricarboxylic acid cycle, oxidative phosphorylation, and fatty acid/amino acid synthesis and degradation. Particular focus is given to metabolic alterations that contribute to myeloma cell growth, proliferation and drug resistance. Finally, novel approaches that target metabolic pathways for the treatment of MM are discussed.

The role of the PI3K/AKT/mTOR pathway in brain tumor metastasis

The PI3K/AKT/mTOR(PAM)pathway is involved in a variety of cellular functions and often contributes to oncogenesis and cancer progression.It has been recognized that this pathway is frequently activated in the most common central nervous system cancers of adults and children,malignant gliomas and medulloblastomas(MB).In these tumors,the PAM network controls key functions necessary for cell invasion and metastasis,such as cell motility.This review summarizes the current knowledge about the role of PAM signaling in cell invasion and metastasis in gliomas and MB.Current approaches to inhibit cell invasion and metastasis by targeting the PAM pathway will also be discussed.

Cancer stem cells in liver metastasis from colon adenocarcinoma express components of the renin-angiotensin system

Aim: We have recently identified a cancer stem cell (CSC) subpopulations within the tumor nests (TNs) and another within the peritumoral stroma (PTS) in liver metastasis from colon adenocarcinoma (LMCA). This study investigated the expression of components of the renin-angiotensin (RAS): pro-renin receptor (PRR), angiotensin converting enzyme (ACE), and angiotensin II receptor 1 (ATIIR1) and angiotensin II receptor 2 (ATIIR2) in LMCA. Methods: 3,3-Diaminobenzidine (DAB) immunohistochemical (IHC) staining was performed on 16 LMCA samples for PRR, ACE, ATIIR1 and ATIIR2. Immunofluorescence (IF) IHC staining was performed to investigate co-expression of these components of the RAS with SOX2 or OCT4. NanoString analysis (n = 6) and Western blotting (WB,n = 3) were performed on snap-frozen LMCA samples to confirm mRNA and protein expression, respectively. Results: DAB IHC staining showed the expression of PRR, ACE, ATIIR1 and ATIIR2 within all LMCA samples. NanoString analysis and WB confirmed gene and protein expression of these components of the RAS. IF IHC staining demonstrated expression of PRR, ATIIR1 and ATIIR2 by the SOX2+ CSCs within the TNs and the OCT4+ CSCs within the PTS. ACE was expressed on the endothelium of the microvessels within the PTS. ;Conclusion: These finding suggests the CSCs within LMCA maybe a novel therapeutic target by manipulation of the RAS.

Recent advances in immunotherapy for pancreatic cancer

Pancreatic ductal adenocarcinoma(PDAC)remains a disease with a dismal prognosis.Since 1996 there have only been two upfront regimens found to be superior to gemcitabine:FOLFIRINOX(5-fluorouracil,leucovorin,irinotecan and oxaliplatin),and gemcitabine plus nab-paclitaxel.Despite the improvement noted in these trials,PDAC is highly chemo-resistant and patients who respond will inevitably develop resistance.The unique immunosuppressive tumor microenvironment with extensive desmoplasia has posed challenges to developing new and effective treatments.Therapeutic vaccines,combination treatments,adoptive T cell transfer,as well as immunomodulators are being explored.With the emerging use of immunotherapy and immunomodulators,the scope of this review is to present the current data on these agents as well as focus on the advancements in the treatment of PDAC.Overall,results in this realm have been disappointing to date reflecting the non-immunogenic and complex tumor microenvironment of PDAC.

Phytochemicals and cancer chemoprevention

The unending morbidity and mortality that results from cancer,as well as adverse reactions due to chemotherapy and the enormous economic burden of treatment and hospitalization,advocates for the necessity of chemopreventive measures.Cancer chemoprevention refers to the use of agents capable of reversing,reducing,or slowing down the pathology of cancer at various stages.Fortunately,a few therapeutic drugs with relatively low toxicity(e.g.,tamoxifen,finasteride),and a sparse number of vaccines(hepatitis B,HPV),are used to prevent specific cancers.In the general population,however,therapeutic options for cancer prevention are not common.Nonetheless,it is generally agreed that diet affects the genesis of cancer,and phytochemicals have the capacity of functioning as cancer chemoprevention agents.This is supported by epidemiological studies and clearly documented with animal models designed to mimic human carcinogenesis.Additionally,some public health strategies,such as recommendations for greater consumption of fruits and vegetables,reflect the merits of cancer chemoprevention.Here,we focus on some well-established natural product cancer chemopreventive agents,including resveratrol(grapes),epigallocatechin-3-gallate(green tea),sulforaphane(cruciferous vegetables),anthocyanins(grapes and berries),curcumin(turmeric),silibinin(milk thistle),and lycopene(tomatoes).As aptly demonstrated by genomic analysis and other methods,the mechanistic underpinning is variable and complex.In addition,responses may be mediated through indirect mechanisms,such as interaction with the microbiome.Furthermore,ancillary applications of chemopreventive agents are worthy of consideration,such as management of sequelae induced by chemotherapy.Recognizing the loss of millions of cancer patients every year,it is obvious that negating malignant metastatic conditions remains of paramount importance.In meeting this objective,cancer chemoprevention offers great promise.

ESR1 alterations and metastasis in estrogen receptor positive breast cancer

Endocrine therapy is essential for the treatment of patients with estrogen receptor positive (ER+) breast cancer, however, resistance and the development of metastatic disease is common. Understanding how ER+ breast cancer metastasizes is critical since the major cause of death in breast cancer is metastasis to distant organs. Results from many studies suggest dysregulation of the estrogen receptor alpha gene (ESR1) contributes to therapeutic resistance and metastatic biology. This review covers both pre-clinical and clinical evidence on the spectrum ofESR1 alterations including amplification, point mutations, and genomic rearrangement events driving treatment resistance and metastatic potential of ER+ breast cancer. Importantly, we describe how these ESR1 alterations may provide therapeutic opportunities to improve outcomes in patients with lethal, metastatic breast cancer.

Central regulation of breast cancer growth and metastasis

Cancer is a systemic disease. In order to fully understand it, we must take a holistic view on how cancer interacts with its host. The brain monitors and responds to natural and aberrant signals arriving from the periphery, particularly those of metabolic or immune origin. As has been well described, a hallmark of cancer is marked disruption of metabolic and inflammatory processes. Depending on the salience and timing of these inputs, the brain responds via neural and humoral routes to alter whole-body physiology. These responses have consequences for tumor growth and metastasis, directly influencing patient quality of life and subsequent mortality. Additionally, environmental inputs such as light, diet, and stress, can promote inappropriate neural activity that benefits cancer. Here, I discuss evidence for brain-tumor interactions, with special emphasis on subcortical neuromodulator neural populations, and potential ways of harnessing this cross-talk as a novel approach for cancer treatment.

Cancer, circulating tumor cells, and metastasis: could protein-derived peptide fragments impede brain metastases?

The majority of cancer deaths can be attributed to cancer cell metastases that migrate to distant target organs.Brain metastases constitute one of the leading causes of morbidity and mortality among cancer patients,occurring in about 40%of patients with metastatic disease.Thus,there exists an unmet need for early detection,diagnosis,and treatment directed against early stage cancer cell metastasis.Previous studies have reported the development of methods to detect and identify early circulating tumor cells(CTCs)in the bloodstream prior to their seeding into distant organs.Using a comprehensive analysis of total CTCs mRNA content,investigators have developed a mRNA“transcriptome signature”of 126 genes involved in CTC metastatic events.The genes were parsed into various metastatic-related activities indicating that CTCs sustained a semi-dormancy state bent on:(1)stress survival;(2)metabolic maintenance;(3)DNA and translational stability;and(4)chemotactic pro-inflammatory capabilities.These activities suggested that CTCs might be susceptible to interactions with protein-derived peptide segments whose actions are involved with metastatic activities such as cell invasiveness,contact,adhesion,motility,spreading,and migration.The use of protein-derived(encrypted)peptides to impede CTC metabolic activities and disrupt signaling pathways could have therapeutic potential in patients with early metastatic disease.

Perspective on dietary isothiocyanates in the prevention,development and treatment of cancer

Epidemiological evidence has highlighted the association of specific diets and a lower incidence of cancer.Foremost,the Mediterranean diet provides high levels of polyphenolics and a high consumption of healthier fats,e.g.,as from olive oil.In the Mediterranean region the consumption of vegetables is elevated providing a class of compounds,the isothiocyanates(ITCs)as found in the cabbage family.The ITCs have raised great interest for their health benefits over the past few decades.Some of the key ITC compounds,sulforaphane,phenethylisothiocyanate and benzyl isothiocyanate,have been studied in vitro and in vivo and the data support their promise for cancer chemoprevention,as anti-tumor agents,and for chemoprotection of normal tissues and organs.Along with other polyphenolic compounds in the diet,in general,they also possess key anti-inflammatory properties thus satisfying the criteria for compounds that could intervene in cancer initiation and progression.In this review we provide a larger overview of the advantages of including ITCs in the diet as food or as supplements and speculate on what could constitute a valuable therapeutic strategy for improving and sustaining good health and countering cancer disease in humans.

Liquid biopsy in endometrial cancer

Liquid biopsy(LB)is an emerging tool for the evaluation of relapse in several cancers and nowadays is used in lung cancer for primary detection and molecular characterization when tumoral tissue is not available.It can represent an innovative biospecimen for the screening,diagnosis,and monitoring of all types of cancer and for monitoring of therapeutic efficacy.LB includes several biofluids such as blood,urine,peritoneal fluid/lavage,and analytes(circulating tumor cells,circulating tumor DNA,long noncoding RNA,microRNA,vesicles,mRNA,and protein)that can play different roles in diagnosis,prognosis,and patient management as well as in the improvement of the knowledge of cancer evolution.Endometrial cancer(EC)is a tumor usually detected at low stage with a good prognosis,but few low risk cases,unexpectedly,can evolve to bad prognosis.Up to now,no molecular target exists to treat advanced stage or to define the evolution of low stage EC.This review focuses on how the LB may help in the management and characterization of patients affected by EC.

Are memantine, methylphenidate and donepezil effective in sparing cognitive functioning after brain irradiation?

One strategy to reduce neurocognitive deterioration in patients after brain irradiation is the use of neuroprotective medication.To generate up-to date knowledge regarding neuroprotective agents we performed a systematic review on the clinical effectiveness of three agents that were reported to have neuroprotective characteristics:memantine,methylphenidate and donepezil.The use of memantine after brain irradiation showed a delay in cognitive deterioration,although at 24 weeks this did not reach significance(P=0.059).Lack of significance is likely to be the result of the limited statistical power of 35%and memantine did show significant differences in secondary outcomes.The study on methylphenidate was not conclusive.Donepezil revealed significant differences in a few cognitive tests however no difference in global cognition was found.In addition,larger effects were observed in individuals with greater cognitive dysfunction prior to treatment.

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

Cancer immunotherapy has now been conclusively shown to be capable of producing durable responses for a substantial number of patients.Adoptive cell transfer and checkpoint blockade therapies in particular both demonstrate that antigen-specific immune responses can be dramatically effective,even in previously refractory late stage disease.Such developments,together with advances in technology,have strongly encouraged revisiting the concept of neoantigen vaccines.Here we introduce basic ideas in the field to allow investigators from diverse backgrounds to understand these developments,grasp current issues,and contribute to further progress.