Immune checkpoint inhibitors (ICI) have become a focus and hope for the future in cancer therapy, while the potential of ICI for the treatment of chronic infections is only beginning to be assessed. The heterogeneity and complexity of cancers make ICI favorable to be developed as personalized medicine to suit individual needs. However, not every patient has benefited as response rates are still inadequate and ICIs are limited by immune-related adverse events and toxicities as well as complications from increased risk of infection. These failures may be due to immune variations from aging as well as genetic differences such as sex.

Sex hormones, including estrogen, progesterone, and androgens, are steroid hormones with a substantial impact on the immune system. Estrogen demonstrates both pro- and anti-inflammatory roles while progesterone and androgens are mainly anti-inflammatory. Sex hormones share a common biosynthetic pathway with glucocorticoids, a group of strong anti-inflammatory agents in the body, which predicts interactions with consequences on immune response.

In addition, the sex chromosomes also harbor many other immune-related genes. Toll-like receptors, cytokine receptors involved in T-cell and B-cell activity are localized to the X chromosome and inflammatory pathway genes in Y. These sex-based immunological differences contribute to variations in incidence of immune-related conditions such as autoimmune and cardiovascular diseases. Females defend better against infectious diseases and possibly malignancies and have superior respond to vaccines. Clearly, variations are expected in other immune-based therapies including ICIs.

Early studies on the efficacy of ICI suggest males respond better, achieving improved overall survival (OS) and progression-free survival (PFS) from therapy with PD-1/PD-L1 inhibitors in melanoma and NSCLC. Increased frequencies of PD-1 expressing CD4+ T cells among males may be a contributory factor.

Aging, on the other hand, impairs immunity with the production of new immune cells beginning to diminish, a higher basal level of inflammatory factors in the elderly promoting inflammatory diseases in the cardiovascular system and neurodegenerative diseases, reducing the ability to fight cancers and infections.

Thus, age and sex may alter the intensity of immune response, increasing or decreasing thresholds to cross over, which are crucial in deciding the final outcome in immune-based treatment modalities. Indeed, the elderly appear to tolerate ICI similar to younger patients but lower efficacy has been seen in certain cancers.

Nevertheless, we may only be scratching the surface with these targets as the immune system is complex and well known for its redundancy and multiplicity. New targets may extend to innate immunity as the cells are just as capable to fight cancers and infections and respond under regulation and control. Ultimately, in our efforts to retrain the immune system to regain its protective ability against cancers and infections, it is worthwhile to consider also the need to overcome age and sex factors.

In this Research Topic we welcome authors to submit Reviews, Mini-Reviews, Original Research, Perspective, and Clinical Trial articles focusing on, but not limited to, the following subtopics:

1) Molecular/cellular immune checkpoint differences due to age or sex

2) Role of sex hormones in differential efficacy of Immune Checkpoint Inhibitors

3) Sex-differences in the immune response and adverse reactions to Immune Checkpoint Inhibitors

4) Age-related immune differences in affecting outcome of immune checkpoint inhibitors

5) Safety and efficacy of ICI in elderly people with cancers and infections such as malaria, HIV, HBV or SARS-CoV-2

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Frontiers in Immunology

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