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Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells in Prostate Adenocarcinoma and Melanoma.

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.

SUBMITTER: Elia AR

PROVIDER: S-EPMC6079266 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells in Prostate Adenocarcinoma and Melanoma.

Elia Angela Rita AR Caputo Sara S Bellone Matteo M

Frontiers in immunology 20180731

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, res ...[more]

PMID: 30108594

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Project description:ImportanceImmune checkpoint inhibitors (ICIs) have revolutionized melanoma treatment and are now standard of care. Although sex is associated with immune function and immune-related diseases, the interaction between sex and ICIs is understudied.ObjectiveTo examine whether cancer immunotherapy effectiveness varies between female and male patients with advanced melanoma treated with either nivolumab plus ipilimumab combination therapy or anti-programmed cell death protein 1 (PD-1) therapy (namely, pembrolizumab or nivolumab).Design, setting, and participantsThe study population consisted of 1369 older adults (aged ≥65 years) with a record of melanoma diagnosis from January 1, 1991, to December 31, 2015, in the Surveillance, Epidemiology, and End Results-Medicare linked database. Patients with a diagnosis of stage III or stage IV melanoma and a claims record showing nivolumab plus ipilimumab combination therapy or anti-PD-1 therapy (ie, pembrolizumab or nivolumab) as their last type of ICI prescribed were included in the analyses. Patients were followed up through December 31, 2017, for the overall survival analysis. Statistical analysis was performed from September 19, 2019, to February 20, 2021.ExposuresSex, last prescribed ICI, and prior use of ipilimumab.Main outcomes and measuresThe primary outcome was overall survival, defined as time from the index date until death from any cause, with patients censored at the end of the study (December 31, 2017). Cox proportional hazards regression modeling was used to examine the association of sex with ICI outcomes while adjusting for prior use of ipilimumab, age at ICI initiation, Charlson Comorbidity Index, cancer stage at the time of diagnosis, and autoimmune disease diagnosis.ResultsAmong the 1369 patients in the study (982 men [71.7%]; median age, 75 years [IQR, 69-82 years]), the outcome of nivolumab plus ipilimumab combination therapy depended on sex (Wald χ2 = 9.48; P = .009 for interaction). The mortality hazard ratio (HR) for women with prior ipilimumab use receiving combination therapy was 2.06 times (95% CI, 1.28-3.32; P = .003) higher than their male counterparts. No significant difference was observed between women and men receiving anti-PD-1 therapy with (HR, 0.97 [95% CI, 0.68-1.38]; P = .85) or without prior ipilimumab use (HR, 0.85 [95% CI, 0.67-1.07]; P = .16). For women with prior ipilimumab use, combination therapy was associated with 2.82 times higher mortality hazards than anti-PD-1 therapy (95% CI, 1.73-4.60). No statistically significant difference was seen in mortality risk between anti-PD-1 therapy and combination therapy for men.Conclusions and relevanceThis cohort study suggests that female patients with advanced melanoma may not benefit as much from combination ICIs as male patients would. Tumor mutation burden or estrogen level may serve as an important biomarker associated with ICI response in metastatic melanoma.

Dataset Information

Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells in Prostate Adenocarcinoma and Melanoma.

Publications

Immune Checkpoint-Mediated Interactions Between Cancer and Immune Cells in Prostate Adenocarcinoma and Melanoma.

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