Decades of population health data reveal that cancer incidence and mortality is greater in men compared to women in nearly all tumors of non-reproductive tissues. In the past few years, there has been an explosion of research investigating how features of an individual’s sex (sex chromosomes, sex hormones, social determinants of health, etc) contribute to this disease risk difference. The purpose of this meeting was to bring together experts from across the country who are thinking about this question from unique perspectives.  

The meeting was attended by 12 investigators. Two scholars were initially registered; however, due to changes in federal funding and university travel restrictions, these scholars were unable to join us. The group of investigators spanned the spectrum of the investigation of sex differences in cancer. Dr. Quinn Ostrom from Duke University presented epidemiological observations from population health studies on correlations between allergies, autoimmunity, and brain cancer risk. Notably, whereas hay fever allergies lowered overall risk of brain cancer for both men and women,autoimmunity (specifically RA or SLE) was only protective in female against high grade gliomas. Dr. Hannah Carter (University of California, San Diego)also leveraged population health data to generate polygenic risk scores associated with response to immunotherapy and found that these were different between men and women. Notably, female tumors had fewer neoantigens compared to male tumors.

These observations were complemented by mouse model studies by Drs. Justin Lathia (Cleveland Clinic), Elise Alspach (Saint Louis University), and Kyuson Yun (Houston Methodist) who outlined sex differences in innate and adaptive immune responses (platelets, microglia, astrocytes, and Tcells) in brain and bladder tumors. In both models, female tumors-whether in the brain or the bladder-were enriched for white blood cells that are associated with better overall prognosis, highlighting the differences in immune-cancer interactions in males vs females. On this topic, Dr. Defne Bayik (University of Miami) shared a key sex difference in a subset of these innate white blood cells called myeloid derived suppressor cells (MDSCs), in their expression of neurotransmitter receptors. This signaling difference informed sex-specific immunosuppressive mechanisms. Other attendees at the meeting including Drs. Laura St. Clair (Johns Hopkins University) and Joseph Ippilito (Washington University St. Louis) revealed key metabolic differences in immune and tumor cells from male and females. The key takeaway, that famine favors female, became a recurring catch-phrase throughout the meeting!

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Dr. Katie Basham from the University of Utah challenged many of the paradigms discussed at the meeting by presenting data on adrenal cancers which are twice as common in females compared to males. Her research focused on sex differences, mediated by androgens rather than glucocorticoids, in regulating macrophage trafficking and function in male and female adrenal tumors. Also leveraging the immune-modulating function of androgens, Dr. Amy Moran (Oregon Health & Science University) discussed an array of mechanisms by which testosterone blockade can activate the immune system-from thymic regeneration to enhanced innate and adaptive immune responses and synergy with immunotherapy.

Finally, in a fascinating lecture from Dr. Sri Viswanathan (Dana Farber Cancer Institute), the group learned about X-linked genetic factors that underlie sex differences in cancer. Leveraging a unique gene fusion between an X-linked gene (TFE3) with a gene on an autosome (non-sex chromosome), he revealed a sex-chromosome mediated mechanism of kidney cancer (renal cell carcinoma). Interestingly, he raised the possibility that in XX individuals, if the ‘inactive’ X-chromosome forms a translocation with a gene on an autosome, such as a tumor suppressor gene, then it’s possible to have X-linked gene silencing of non-X genes. Dr Viswanathan’s talk was the final one of the meeting, reducing some sex differences down to sex chromosomes!

The group finished the meeting with a brainstorming session on defining what we mean when we talk about sex differences. We discussed the importance of specifying hormone-mediated or chromosome-mediated differences,observation based on age, and/or simply sex organs displayed by an organism. New friendships and collaborations were forged and all agreed that this intimate‘think tank’ meeting was one of the best we’d ever attended!