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Abstract
Background: Immunotherapies targeting immune checkpoint proteins CTLA-4, PD-1, and PD-L1 have saved lives, but these therapies have only been effective in some patients. Patients positive for expression of immune checkpoint proteins in the tumor microenvironment show better response to immune checkpoint inhibitors. Consequently, knowledge of which genes are consistently expressed in lymphocytes within the tumor microenvironment can convey potentially effective and complementary new immunotherapy targets. Results: We identified 54 genes that have higher co-expression with the pan T-cell marker CD3E than CTLA4 or PDCD1. In a dataset of 26 patients who received anti-PD-1 therapy, we observed that co-expression between CD3E and PDCD1 was higher among responders than non-responders, supporting our correlation-based approach. Conclusions: The genes highlighted in these analyses, which include CD6, TIGIT, CD96, and SLAMF6, warrant further investigation of their therapeutic potential. Methods: We analyzed and ranked genes that were co-expressed with the pan T-cell marker CD3E in 9,601 human tumors, spanning 31 cancer types. To further identify targets that may be complementary to existing PD-1 therapy, we examined and ranked genes with high CD3E co-expression and relatively low PDCD1 co-expression.
Highlights
The long-term effectiveness of broad-spectrum chemotherapies [1] and molecularly-targeted therapies [2] is mitigated by the evolutionary dynamics of tumor cells, wherein natural selection favors increasingly aggressive and drug-resistant clones
In a dataset of 26 patients who received antiPD-1 therapy, we observed that co-expression between CD3E and PDCD1 was higher among responders than non-responders, supporting our correlation-based approach
The genes highlighted in these analyses, which include CD6, TIGIT, CD96, and SLAMF6, warrant further investigation of their therapeutic potential
Summary
The long-term effectiveness of broad-spectrum chemotherapies [1] and molecularly-targeted therapies [2] is mitigated by the evolutionary dynamics of tumor cells, wherein natural selection favors increasingly aggressive and drug-resistant clones. Therapeutic resistance presents one of the universal challenges in cancer treatment and can be attributed to the extensive genetic [3] and phenotypic [4] diversity present within tumor cell populations. The promise of immunomodulatory approaches lies in the potential to confront one dynamic, diversity-rich system (the evolving tumor) with another (the adaptive immune system) [11,12,13,14]. Immunotherapies targeting immune checkpoint proteins CTLA-4, PD-1, and PD-L1 have saved lives, but these therapies have only been effective in some patients. Patients positive for expression of immune checkpoint proteins in the tumor microenvironment show better response to immune checkpoint inhibitors. Knowledge of which genes are consistently expressed in lymphocytes within the tumor microenvironment can convey potentially effective and complementary new immunotherapy targets
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