Strength of immune selection in tumors varies with sex and age

Castro, Andrea; Pyke, Rachel Marty; Zhang, Xinlian; Thompson, Wesley K.; Day, Chi-Ping; Alexandrov, Ludmil B.; Zanetti, Maurizio; Carter, Hannah

doi:10.1038/s41467-020-17981-0

Cited by 86 publications

(73 citation statements)

References 49 publications

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“…Various chemotherapy regimens show higher toxicity, higher response rates, and longer post-treatment survival in women, including lymphoma (2), sarcoma (3), glioblastoma (4), lung (5,6), and colorectal (7) cancers. There is also a growing literature showing cancer immunotherapy efficacy varies by sex (8)(9)(10)(11)(12)(13). Poorer response rates are usually reported in females compared to males.…”

Section: Introductionmentioning

confidence: 99%

Genome-Wide Sex and Gender Differences in Cancer

2020

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Despite their known importance in clinical medicine, differences based on sex and gender are among the least studied factors affecting cancer susceptibility, progression, survival, and therapeutic response. In particular, the molecular mechanisms driving sex differences are poorly understood and so most approaches to precision medicine use mutational or other genomic data to assign therapy without considering how the sex of the individual might influence therapeutic efficacy. The mandate by the National Institutes of Health that research studies include sex as a biological variable has begun to expand our understanding on its importance. Sex differences in cancer may arise due to a combination of environmental, genetic, and epigenetic factors, as well as differences in gene regulation, and expression. Extensive sex differences occur genome-wide, and ultimately influence cancer biology and outcomes. In this review, we summarize the current state of knowledge about sex-specific genetic and genome-wide influences in cancer, describe how differences in response to environmental exposures and genetic and epigenetic alterations alter the trajectory of the disease, and provide insights into the importance of integrative analyses in understanding the interplay of sex and genomics in cancer. In particular, we will explore some of the emerging analytical approaches, such as the use of network methods, that are providing a deeper understanding of the drivers of differences based on sex and gender. Better understanding these complex factors and their interactions will improve cancer prevention, treatment, and outcomes for all individuals.

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Section: Introductionmentioning

confidence: 99%

Genome-Wide Sex and Gender Differences in Cancer

2020

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“…Similarly, the prognostically favourable association of tumour infiltrating lymphocytes (TILs) is long-established, but factors controlling T cell infiltration remain unresolved (6, 7) . Crucially, it is increasingly apparent that general aspects of immune function may play a critical, yet comparatively under-investigated role in determining tumour recognition and control (8) .…”

Section: Introductionmentioning

confidence: 99%

Sensitivity to Immune Checkpoint Blockade and Progression-Free Survival is associated with baseline CD8⁺T cell clone size and cytotoxicity

Watson

Tong

et al. 2020

Preprint

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Immune checkpoint blockers (ICB) exert their anti-cancer effects via CD8+ T cells, although how responses vary over sub-populations and across clones is incompletely understood. We performed single-cell RNA-sequencing of CD8+ T cells and their receptors pre and post ICB across eight patients, integrating results with bulk-sequencing data (n=169). We identify seven phenotypic subsets with divergent sensitivity to ICB, finding the effector subset demonstrates the most pronounced changes. ICB response was related to clone size, with small and large clones markedly differing in the magnitude and immunological relevance of regulated genes. ICB upregulates mitotic pathways and promotes expansion and survival of larger, more cytotoxic clones. Notably, baseline cytotoxicity, but not correlates of mitosis, associated with progression-free survival; highlighting the importance of the pre-treatment CD8+ immune landscape in long-term response. This work further advances understanding of the molecular determinants of ICB response and assists in the search for peripheral prognostic biomarkers.

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“…These differences are associated with sex differences in molecular markers, such as tumor mutational burden, neoantigen load, PD-L1 expression, and density of both anti-and pro-tumor immune cells ( Figure 4A) [400]. In line with this, older cancer patients and males have a better antigen presentation on their tumor cells than female and younger patients, resulting in better immune system detection and response to immune checkpoint blockade therapies [401].…”

Section: Patient Characteristics That Can Improve Response Rates To Imentioning

confidence: 77%

Overcoming Immune Evasion in Melanoma

Eddy

Chen

2020

IJMS

134

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Melanoma is the most aggressive and dangerous form of skin cancer that develops from transformed melanocytes. It is crucial to identify melanoma at its early stages, in situ, as it is “curable” at this stage. However, after metastasis, it is difficult to treat and the five-year survival is only 25%. In recent years, a better understanding of the etiology of melanoma and its progression has made it possible for the development of targeted therapeutics, such as vemurafenib and immunotherapies, to treat advanced melanomas. In this review, we focus on the molecular mechanisms that mediate melanoma development and progression, with a special focus on the immune evasion strategies utilized by melanomas, to evade host immune surveillances. The proposed mechanism of action and the roles of immunotherapeutic agents, ipilimumab, nivolumab, pembrolizumab, and atezolizumab, adoptive T- cell therapy plus T-VEC in the treatment of advanced melanoma are discussed. In this review, we implore that a better understanding of the steps that mediate melanoma onset and progression, immune evasion strategies exploited by these tumor cells, and the identification of biomarkers to predict treatment response are critical in the design of improved strategies to improve clinical outcomes for patients with this deadly disease.

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Strength of immune selection in tumors varies with sex and age

Cited by 86 publications

References 49 publications

Genome-Wide Sex and Gender Differences in Cancer

Genome-Wide Sex and Gender Differences in Cancer

Sensitivity to Immune Checkpoint Blockade and Progression-Free Survival is associated with baseline CD8⁺T cell clone size and cytotoxicity

Overcoming Immune Evasion in Melanoma

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Strength of immune selection in tumors varies with sex and age

Cited by 86 publications

References 49 publications

Genome-Wide Sex and Gender Differences in Cancer

Genome-Wide Sex and Gender Differences in Cancer

Sensitivity to Immune Checkpoint Blockade and Progression-Free Survival is associated with baseline CD8+T cell clone size and cytotoxicity

Overcoming Immune Evasion in Melanoma

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Product

Resources

About

Sensitivity to Immune Checkpoint Blockade and Progression-Free Survival is associated with baseline CD8⁺T cell clone size and cytotoxicity