Mechanistic insights of cancer immunology have led to the development of immune checkpoint blockade therapy (ICBT), which has elicited a remarkable clinical response in some cancer patients. Increasing evidence suggests that activation of oncogenic pathways, such as RAS/RAF/MAPK and PI3K signaling, impairs the antitumor immune response. Such oncogenic signaling, in turn, activates many inhibitory factors, including expression of immune checkpoint genes—allowing active infiltration of immunosuppressive cells into the tumor environment and inducing resistance against T-cell killing. In preclinical tumor models, effective targeting of oncogenic pathways has enhanced the response to ICBT. Ongoing clinical trials are now evaluating combination therapy (i.e., the use of oncogenic pathway inhibitors in combination with ICBT). However, more translational and clinical research is needed, to optimize ICBT doses and sequence, minimize toxicity, and assess the impact on study participants of certain genetic backgrounds. Also, it is crucial to understand whether wild-type tumors with elevated oncogenic signaling will respond to combination therapy. Insights gained through current and future translational studies will provide the scientific premise and rationale to target 1 or more oncogenic pathways in ICBT-resistant tumors, thus enabling more human patients to benefit from combination therapy.
Bibliographical noteFunding Information:
We thank Dr. Mary Knatterud for assisting in manuscript preparation. Because of space restrictions, we cannot cite many other significant contributions made by numerous researchers and laboratories in this potentially important and rapidly progressing field. SS is supported by research grants funded by the American Cancer Society (grant RSG 13-381-01-RMC ). XZ is supported by a research fellowship from the Department of Surgery, University of Minnesota.
- Antitumor immune response
- Cancer immunotherapy
- Combination therapy
- Immune checkpoint blockade therapy
- Oncogenic pathways