The aged tumor microenvironment limits T cell control of cancer

Alex C Y Chen; Sneha Jaiswal; Daniela Martinez; Cansu Yerinde; Keely Ji; Velita Miranda; Megan E Fung; Sarah A Weiss; Maria Zschummel; Kazuhiro Taguchi; Christopher S Garris; Thorsten R Mempel; Nir Hacohen; Debattama R Sen

doi:10.1038/s41590-024-01828-7

The aged tumor microenvironment limits T cell control of cancer

Nat Immunol. 2024 May 14. doi: 10.1038/s41590-024-01828-7. Online ahead of print.

Authors

Alex C Y Chen^{1

2

3

4}, Sneha Jaiswal^#^{1

5}, Daniela Martinez^#^{1

2

3

4}, Cansu Yerinde^{1

2

3

4}, Keely Ji^{1

2

3

4}, Velita Miranda¹, Megan E Fung⁶, Sarah A Weiss⁶, Maria Zschummel^{1

2

3

4}, Kazuhiro Taguchi^{2

4}, Christopher S Garris^{7

8}, Thorsten R Mempel^{2

4}, Nir Hacohen^{1

2

3}, Debattama R Sen^{9

10

11

12}

Affiliations

¹ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA.
² Department of Medicine, Harvard Medical School, Boston, MA, USA.
³ Broad Institute of MIT and Harvard, Cambridge, MA, USA.
⁴ Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA.
⁵ Carnegie Mellon University, Pittsburgh, PA, USA.
⁶ Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
⁷ Center for Systems Biology, Massachusetts General Hospital, Boston, MA, USA.
⁸ Department of Pathology, Harvard Medical School, Boston, MA, USA.
⁹ Krantz Family Center for Cancer Research, Massachusetts General Hospital, Boston, MA, USA. dsen@mgh.harvard.edu.
¹⁰ Department of Medicine, Harvard Medical School, Boston, MA, USA. dsen@mgh.harvard.edu.
¹¹ Broad Institute of MIT and Harvard, Cambridge, MA, USA. dsen@mgh.harvard.edu.
¹² Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA, USA. dsen@mgh.harvard.edu.

^# Contributed equally.

PMID: 38745085
DOI: 10.1038/s41590-024-01828-7

Abstract

The etiology and effect of age-related immune dysfunction in cancer is not completely understood. Here we show that limited priming of CD8⁺ T cells in the aged tumor microenvironment (TME) outweighs cell-intrinsic defects in limiting tumor control. Increased tumor growth in aging is associated with reduced CD8⁺ T cell infiltration and function. Transfer of T cells from young mice does not restore tumor control in aged mice owing to rapid induction of T cell dysfunction. Cell-extrinsic signals in the aged TME drive a tumor-infiltrating age-associated dysfunctional (T_TAD) cell state that is functionally, transcriptionally and epigenetically distinct from canonical T cell exhaustion. Altered natural killer cell-dendritic cell-CD8⁺ T cell cross-talk in aged tumors impairs T cell priming by conventional type 1 dendritic cells and promotes T_TAD cell formation. Aged mice are thereby unable to benefit from therapeutic tumor vaccination. Critically, myeloid-targeted therapy to reinvigorate conventional type 1 dendritic cells can improve tumor control and restore CD8⁺ T cell immunity in aging.

Abstract

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