Younger Women Less Likely to Respond to Immunotherapy

This paper is really at the edge of my ability to interpret immunology data, but I am a fascinated and eager student all the same. The authors looked at the immunologic landscape of tumor samples across age and sex, reporting not just on the presence of somatic driver mutations but how visible those mutations are to the immune system.

With variable rates of response to checkpoint inhibitors (the authors cite 10-40% overall) the paper explores immune escape, and notes specifically how that process is stacked against younger, and particularly female, patients. From a cohort of TGCA samples, the authors deduced that immune pressure early in tumorigenesis leads to expression of driver mutations that are less visible to the immune system. This process of immunoediting leaves a checkpoint inhibitor nothing to identify and feast upon. They single out thyroid carcinoma and low-grade gliomas as the most pressured and note that these samples represented the lowest average ages at diagnosis. A quick pubmed check revealed that the use of pembro in the 59% female KEYNOTE-028 trial yielded a 9% ORR, which, in the context of this paper, is not especially surprising.

The effect of immunoediting is depicted more clearly here:

Castro et al., Nature Communications

You don’t see too much discussion in cancer about how the aging, weakening immune system actually favors a positive outcome, but here you go. This has already been observed in clinical practice. Who is our model checkpoint inhibitor patient? An old guy with NSCLC (note that the average age of a newly diagnosed NSCLC patient is around 70, with slightly more men than women diagnosed each year). Thyroid cancer and LGGs were discussed earlier, but the last line could also belong to TNBC patients, who tend to be diagnosed between 40 and 50 and are among the problem children of immunotherapy with their “cold” tumors. We know from IMpassion that we can treat TNBC patients with an atezo-Abraxane combo, but that program has always felt like work, hasn’t it? Now we have a little more insight into why.

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