Abstract
Prostate adenocarcinoma (PCa) and melanoma are paradigmatic examples of tumors that are either poorly or highly sensitive to therapies based on monoclonal antibodies directed against regulatory pathways in T lymphocytes [i.e., immune checkpoint blockade (ICB)]. Yet, approximately 40% of melanoma patients are resistant or acquire resistance to ICB. What characterize the microenvironment of PCa and ICB-resistant melanoma are a scanty cytotoxic T cell infiltrate and a strong immune suppression, respectively. Here, we compare the tumor microenvironment in these two subgroups of cancer patients, focusing on some among the most represented immune checkpoint molecules: cytotoxic T lymphocyte-associated antigen-4, programmed death-1, lymphocyte activation gene-3, and T cell immunoglobulin and mucin-domain containing-3. We also report on several examples of crosstalk between cancer and immune cells that are mediated by inhibitory immune checkpoints and identify promising strategies aimed at overcoming ICB resistance both in PCa and melanoma.
Highlights
Activated T lymphocytes require mechanisms that timely and properly shut them down to prevent excessive damage at the inflammation site
Lymphocyte activation gene-3 may synergize with other immune checkpoints, and the combination of anti-lymphocyte activation gene-3 (LAG-3) and anti-programmed death-1 (PD-1) resulted in more potent inhibition of murine tumor growth than single treatments [54]
T cell immunoglobulin and mucin-domain containing-3 is expressed on dysfunctional, tumor-specific CD8+ T cells in melanoma [60] and Prostate adenocarcinoma (PCa) patients [61], and in ipilimumabtreated melanoma patients, increased expression and frequency of TIM-3 and PD-1 on both peripheral NK and T cells associated with poor prognosis [62]
Summary
Activated T lymphocytes require mechanisms that timely and properly shut them down to prevent excessive damage at the inflammation site. Exhausted CD8+ T cells, expressing high levels of PD-1 and CTLA-4 predicted response to anti-PD-1 in metastatic melanoma patients [21]. Both in mice and humans, the combination of local chemotherapy and systemic ICB increased tumor infiltration by effector T cells, and clinical response rates (NCT01323517) [33].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
