These study findings suggest that the response rate to immune checkpoint blockade may be dependent on the strength of immune selection occurring early in tumorigenesis.
A study published in Nature Communications found that immune selection exerts its toll differently with regard to sex and age, with a greater effect observed in younger females.1
Given this finding, researchers suggested that the response rate to immune checkpoint blockade (ICB) may be dependent on the strength of immune selection occurring early in tumorigenesis. Moreover, the investigators indicated that methods to accurately predict the impact of immunoediting on a patient-specific basis may lead to better predictive algorithms for response to therapy.
“Now that we know why some patients don’t respond as well to immunotherapy, we can begin developing more informed approaches to treatment decisions — for instance, developing predictive algorithms to determine a person’s likely response before initiating immunotherapies that may have a high probability of not working or working poorly for them,” senior author Hannah Carter, PhD, associate professor of medicine at UC San Diego School of Medicine, said in a press release.2
In this study, researchers evaluated genomic information from 9913 patients with cancer available from the National Institutes of Health’s Cancer Genome Atlas, and another 342 patients with other tumor types available from the International Cancer Genome Consortium database and published studies.
Overall, no differences were observed with regard to age or sex-related differences for major histocompatibility complex (MHC) function. However, compared to older and male patients with cancer, younger and female patients generally accumulated more cancer-causing genetic mutations of which MHCs cannot present to the immune system as efficiently.
“This shows an important thing, that the interplay between the cancer genome and the adaptive arm of the immune system is not a static one,” co-author Maurizio Zanetti, MD, professor of medicine at UC San Diego School of Medicine and head of the Laboratory of Immunology at UC San Diego Moores Cancer Center, said in the release. “Two simple but important variables, age and sex, influence this interplay. The study also emphasizes the master role of the MHC in dictating the outcome of this interplay, reaffirming its central role in the evolution of disease, cancer included, at the level of the individual and population.”
Notably though, the researchers cautioned that the results observed in younger patients do not necessarily apply to children, as the genomic landscape of pediatric tumors differs greatly from adulthood tumors, with lower mutation burdens, different driver events, and more germline factors. In addition, similar to most genomic databases, the genomic information used in this study contained data primarily from individuals of caucasian descent, and more diversity is needed to confirm that the findings can be generalized to all populations.
“Cancer isn’t just one disease, and so the way we treat it can’t be one-size-fits-all,” she said. “All checkpoint inhibitors can do is remove the generic block that tumors put up to hide from the immune system. The more we learn about how interactions between tumors and immune systems might vary, the better positioned we are to tailor treatments to each person’s situation.”
1. Castro A, Pyke RM, Zhang X, et al. Strength of immune selection in tumors varies with sex and age. Nature Communications. doi: 10.1038/s41467-020-17981-0
2. Why Young and Female Patients Don’t Respond as Well to Cancer Immunotherapy [news release]. UC San Diego Health. Published August 17, 2020. Accessed August 20, 2020. https://health.ucsd.edu/news/releases/Pages/2020-08-17-why-young-and-female-patients-dont-respond-as-well-to-cancer-immunotherapy.aspx#:~:text=Their%20findings%20suggest%20that%20since,some%20types%20of%20immunotherapy%20ineffective.