Dear Colleagues,

Checkpoint (co-inhibitory) pathways were originally defined by their ability to inhibit or dampen T cell mediated responses. Preclinical studies in tumor models and clinical trials demonstrated that blocking of the prototype inhibitory pathway, CTLA-4 and its ligands CD80 and CD86, lead to tumor regression primarily in melanoma. This resulted in the first FDA approved checkpoint inhibitor, Ipilimumab (YERVOY®), an antibody targeting CTLA-4. The discovery of PD-1 in the early 1990s and later its ligands PD-l, and PD-L2 was the first hint that there were additional members of the checkpoint family which were distinct in functionality from CTLA-4. The wide-ranging expression of PD-1 ligands in particular PD-L1 on non-immune cells pointed to the broad immunoregulatory role of the PD-1-PDL pathway in maintaining self-tolerance. In addition, the high expression of PD-1 on ‘exhausted’ T cells in the context of non-functional antigen-specific CD8⁺ T cells in anti-viral immunity and within the tumor microenvironment, together with expression of PD-L1 on tumors suggested the possibility that blocking the PD-1-PD-L1 axis would result in an enhanced anti-tumor response. Over the last decade, a plethora of studies including murine tumor models and clinical trials have demonstrated that PD-1 checkpoint inhibitors are capable of enhancing tumor immunity and could lead to subsequent tumor regression. At present, there are five FDA-approved PD-1/PDL1 checkpoint inhibitors, Pembrolizumab (Keytruda®) and nivolumab (Opdivo®) target the PD-1 receptor, and Atezolizumab (Tenectriq®, Avelumab (BAVENCIO®) and Durvalumab ((IMFINZI®) target PD-L1. Compared to the CTLA-4 checkpoint inhibitor, the number of cancer indications that can be treated with PD-1/PD-L1 checkpoint inhibitors have increased including, but not confined to, metastatic non-small cell lung cancer, classical Hodgkin lymphoma and mismatch-repair deficient (dMMR) metastatic colorectal cancer. Although PD-1:PD-L1 inhibitors have proven very successful in some patients, the majority of patients across  a broad range of indications show little or no response to the PD-1/PDL1 checkpoint inhibitors. Although combination of PD-1 and PD-1 ligands with CTLA-4 inhibitors is showing some improvement in the response rate in patients, there are still unanswered questions about which combination(s) will be the most efficacious and how restrictive these combinations will be to certain cancer types.

Therefore, the emphasis of this Special Issue “Combination of PD-1 and PD-1 Ligands in Immune Responses and Cancer Immunotherapies” will be on pre-clinical and clinical studies in various cancers addressing the following topics:

• Combination of PD-1/PDL inhibitors with new co-inhibitory pathways.
• Combination of PD-1/PDL inhibitors with various other treatment modalities including but not limited to vaccines, targeting immunosuppressive cells in the tumor environment and chemotherapy
• Vaccines against Neoantigen in combination of PD-1/PDL inhibitors
• Combination of PD-1/PDL inhibitors and targeting NK cells
• Biomarkers other than PD-L1 that are associated with combination therapies and PD-1/PDL inhibitor responses.

Dr. Yvette E. Latchman
Dr. Nadeem Sheikh
Dr. Hong Tang
Guest Editors

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• PDL1 checkpoint inhibitors and new coinhibitory pathways
• PDL1 checkpoint inhibitors and vaccines
• PDL1 checkpoint inhibitors and neoantigens
• PDL1 checkpoint inhibitors and targeting immunosuppressive cells in tumor
• PDL1 checkpoint inhibitors and NK cells
• PDL1 checkpoint inhibitors and biomarkers