Using an autochthonous lung adenocarcinoma model, Schenkel and Herbst et al. showed that as tumors progressed, the numbers and functionality of tumor antigen-specific TCF-1+CD8+ T cells declined in lungs, but not dLNs. Cycling SlamF6+ and non-cycling SlamF6- TCF-1+CD8+ TILs with shared clonotypes, but distinct transcriptional profiles were identified. The former, emigrants from dLNs, had higher inhibitory receptor expression than the latter, which dominated in late stage disease. In dLNs, tumor-specific dividing CD8+ T cells and cDC1 migrants decreased as tumors progressed; this was reversed by Flt3L+CD40 agonism, which reduced tumor burden.
Contributed by Paula Hochman
ABSTRACT: In tumors, a subset of CD8+ T cells expressing the transcription factor TCF-1 drives the response to immune checkpoint blockade. We examined the mechanisms that maintain these cells in an autochthonous model of lung adenocarcinoma. Longitudinal sampling and single-cell sequencing of tumor-antigen specific TCF-1+ CD8+ T cells revealed that while intratumoral TCF-1+ CD8+ T cells acquired dysfunctional features and decreased in number as tumors progressed, TCF-1+ CD8+ T cell frequency in the tumor draining LN (dLN) remained stable. Two discrete intratumoral TCF-1+ CD8+ T cell subsets developed over time-a proliferative SlamF6+ subset and a non-cycling SlamF6- subset. Blocking dLN egress decreased the frequency of intratumoral SlamF6+ TCF-1+ CD8+ T cells. Conventional type I dendritic cell (cDC1) in dLN decreased in number with tumor progression, and Flt3L+anti-CD40 treatment recovered SlamF6+ T cell frequencies and decreased tumor burden. Thus, cDC1s in tumor dLN maintain a reservoir of TCF-1+ CD8+ T cells and their decrease contributes to failed anti-tumor immunity.
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Brigham and
Author Info: (1) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (2) Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA. (3) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. (4) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. (5) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA. (6) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Radiation Oncology, Massachusetts General Hospital, Boston MA 02114. (7) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA. (8) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA 02114, USA. (9) Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA. (10) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA. (11) Departments of Pathology, Stanford University, Stanford, CA 94305, USA. (12) Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Evergrande Center for Immunologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA. (13) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Broad Institute of MIT and Harvard, 415 Main Street, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: aviv.regev.sc@gmail.com. (14) David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, 500 Main Street, Cambridge, MA 02139, USA; Department of Biology, Massachusetts Institute of Technology, 77 Massachusetts Avenue, Cambridge, MA 02139, USA. Electronic address: tjacks@mit.edu.
