Deciphering How Alterations in DNA Repair Pathways Perturb Cancer Immune Microenvironment

Dear Colleagues,

Immunotherapy is now another effective arrow in the medical oncologist’s bow. The chimeric-antigen receptor (CAR) strategy against specific tumoral epitopes (e.g., CD19) guarantees a prolonged response in hematological malignancy; another immunotherapeutic approach, the immune checkpoint blockade (ICB), has shown remarkable responses in melanoma, lung cancer, and mismatch repair (MMR)-deficient tumors, although only a limited fraction of patients respond to ICB treatments. Defects in the MMR machinery are the origin of genetic alterations, such as single nucleotide variants and small or large DNA deletions, which can be monitored by next-generation sequencing (NGS) and current computational methods. These alterations can be expressed and presented by Major Histocompatibility Complex I (MHCI) to the immune system, promoting immune surveillance and thereby prolonging the overall survival and/or progression-free survival of cancer patients treated with ICBs. However, cells have evolved multiple mechanisms beyond MMR to maintain DNA sequence fidelity and integrity. It is known that alterations in DNA repair mechanisms might spark genomic instability and modify cellular metabolism. Upon progression, tumor cells rely on different metabolic pathways that empower cellular division and survival while creating a tumor microenvironment that is detrimental for immune infiltrates; however, we have evidence that some DNA repair mechanisms, once altered in cancer, might be beneficial for patients when combined with immune therapies. Novel technologies, such as high-throughput sequencing data and modern bioinformatics methods, favor a better characterization of the intrinsic and extrinsic features of the cancer-immune system network.

This Special Issue aims to build a more solid bridge among DNA repair alterations, cancer immune responses, and immune therapies through biochemical and bioinformatics approaches. To this end, the characterization of the molecular mechanisms behind the favorable outcomes of immunotherapy-treated patients and DNA repair defects might be relevant for identifying the biomarkers of response and novel therapeutic strategies.

Dr. Giovanni Germano
Dr. Laura Surace
Dr. Giuseppe Rospo
Guest Editors

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