Fecal transplantation in patient with metastatic melanoma refractory to immunotherapy:A case report

BACKGROUND Immunotherapy has revolutionized the treatment of metastatic melanoma,but a significant proportion of patients still experience treatment resistance.Fecal microbiota transplantation(FMT)has emerged as a potential strategy to overcome immunotherapy resistance by modulating the gut microbiome.CASE SUMMARY We present a case report of a 57-year-old male with metastatic melanoma refractory to immunotherapy who received FMT in combination with antiprogrammed death-ligand 1(PD-L1)immunotherapy(pembrolizumab).After failing multiple lines of treatment,the patient underwent a single FMT procedure by colonoscopy using fecal material from a female metastatic melanoma donor who successfully responded to immunotherapy.Following FMT,the patient demonstrated a response with decreased subcutaneous disease and subsequently underwent surgery to remove the residual disease.Despite a subsequent recurrence in the small bowel that was resected,the patient remained on pembrolizumab without evidence of melanoma recurrence at the time of writing.CONCLUSION The favorable clinical and long-lasting effect we saw in our patient without significant toxicity suggests that this procedure should be considered in similar patients with immunotherapy refractory melanomas.

Circular RNA drives resistance to anti-PD-1 immunotherapy by regulating the miR-30a-5p/SOX4 axis in non-small cell lung cancer

Aim:Circular RNAs are widely and abnormally expressed in human cancer cells,and they participate in cancer progression.However,they have rarely been investigated in the immune evasion of non-small cell lung cancer(NSCLC).Here,we elucidated the function and molecular mechanism of hsa_circ_0020714 in promoting the resistance to anti-PD-1 immunotherapy of NSCLC.Methods:The expression of hsa_circ_0020714 were examined by qRT-PCR.In vivo experiments were executed to investigate the biological function of hsa_circ_0020714 in the sensitivity of NSCLC to anti-PD-1 immunotherapy.The qRT-PCR,fluorescence in situ hybridization,RNA pulldown,RNA immunoprecipitation,and western blot were carried out to investigate the potential regulatory mechanisms of hsa_circ_0020714 in NSCLC immune evasion.Results:The expression of hsa_circ_0020714 was upregulated in NSCLC tissues compared to the paired adjacent non-tumor tissues,and an increased expression of hsa_circ_0020714 was significantly associated with a bad prognosis and resistance to anti-PD-1 immunotherapy in patients with NSCLC.Mechanistically,hsa_circ_0020714 functions as an endogenous miR-30a-5p sponge to enhance SOX4 expression,thereby promoting immune evasion and anti-PD-1 resistance in NSCLC patients.Conclusion:Hsa_circ_0020714 induces the immune evasion and resistance to anti-PD-1 immunotherapy of NSCLC via the miR-30a-5p/SOX4 axis,and may be an promising immunotherapeutic target in NSCLC.

Cancer resistance to immunotherapy: What is the role of cancer stem cells?

Immunotherapy is an emerging form of cancer therapy that is associated with promising outcomes.However,most cancer patients either do not respond to immunotherapy or develop resistance to treatment.The resistance to immunotherapy is poorly understood compared to chemotherapy and radiotherapy.Since immunotherapy targets cells within the tumor microenvironment,understanding the behavior and interactions of different cells within that environment is essential to adequately understand both therapy options and therapy resistance.This review focuses on reviewing and analyzing the special features of cancer stem cells(CSCs),which we believe may contribute to cancer resistance to immunotherapy.The mechanisms are classified into three main categories:mechanisms related to surface markers which are differentially expressed on CSCs and help CSCs escape from immune surveillance and immune cells killing;mechanisms related to CSC-released cytokines which can recruit immune cells and tame hostile immune responses;and mechanisms related to CSC metabolites which modulate the activities of infiltrated immune cells in the tumor microenvironment.This review also discusses progress made in targeting CSCs with immunotherapy and the prospect of developing novel cancer therapies.

Harnessing epithelial-mesenchymal plasticity to boost cancer immunotherapy

Immune checkpoint blockade (ICB) therapy is a powerful option for cancer treatment. Despite demonstrable progress, mostpatients fail to respond or achieve durable responses due to primary or acquired ICB resistance. Recently, tumor epithelial-tomesenchymal plasticity (EMP) was identified as a critical determinant in regulating immune escape and immunotherapy resistancein cancer. In this review, we summarize the emerging role of tumor EMP in ICB resistance and the tumor-intrinsic or extrinsicmechanisms by which tumors exploit EMP to achieve immunosuppression and immune escape. We discuss strategies to modulatetumor EMP to alleviate immune resistance and to enhance the efficiency of ICB therapy. Our discussion provides new prospects toenhance the ICB response for therapeutic gain in cancer patients.

Tumor-intrinsic metabolic reprogramming and how it drives resistance to anti-PD-1/PD-L1 treatment

The development of immune checkpoint blockade (ICB) therapies has been instrumental in advancing the field of immunotherapy. Despite the prominence of these treatments, many patients exhibit primary or acquired resistance, rendering them ineffective. For example, anti-programmed cell death protein 1 (anti-PD-1)/anti-programmed cell death ligand 1 (anti-PD-L1) treatments are widely utilized across a range of cancer indications, but the response rate is only 10%-30%. As such, it is necessary for researchers to identify targets and develop drugs that can be used in combination with existing ICB therapies to overcome resistance. The intersection of cancer, metabolism, and the immune system has gained considerable traction in recent years as a way to comprehensively study the mechanisms that drive oncogenesis, immune evasion, and immunotherapy resistance. As a result, new research is continuously emerging in support of targeting metabolic pathways as an adjuvant to ICB to boost patient response and overcome resistance. Due to the plethora of studies in recent years highlighting this notion, this review will integrate the relevant articles that demonstrate how tumor-derived alterations in energy, amino acid, and lipid metabolism dysregulate anti-tumor immune responses and drive resistance to anti-PD-1/PD-L1 therapy.

The tumor microenvironment of pancreatic adenocarcinoma and immune checkpoint inhibitor resistance: a perplex relationship

Pancreatic cancer is one of the most aggressive cancers with a high mortality rate even among patients with early-stage disease.Although recent studies with novel therapeutic approaches have led to modest improvement in survival outcomes,limited progress is achieved for the use of immunotherapeutics in this challenging cancer.Immune checkpoint inhibitors,thus far,single-agent or in combination,have not yielded significant improvement in survival outcomes except in mismatch repair-deficient pancreatic cancer.The tumor microenvironment of pancreatic cancer has been considered as an attractive target for over a decade based on preclinical studies that suggested it may adversely affect drug delivery and antitumor immunity.In this review article,we elaborate on the biology of pancreatic cancer microenvironment,its highly complicated interaction with cancer cells,and the immune system.We also discuss plausible explanations that led to the failure of immune checkpoint inhibitors as therapeutic agents and the potential impacts of pancreatic cancer stroma on these negative studies.

A review of mechanisms of resistance to immune checkpoint inhibitors and potential strategies for therapy

Immune checkpoint inhibitors(ICIs)have revolutionized the treatment of cancer over the last decade,bringing about a paradigm shift in systemic cancer therapy away from traditional cytotoxic and targeted therapies.While some patients have dramatic treatment responses,it is sobering to note that most tumors are either resistant at the outset,or develop resistance after initial response.A major area of translational and clinical research is in identifying therapeutic strategies to overcome resistance to ICIs.We have performed an in-depth review of the different mechanisms of resistance and potential avenues to overcome resistance through rationally designed combination treatment with ICIs.