Growing evidence suggests that patients with diverse forms of solid tumors (breast, colon, lung, ovarian, renal and head-and-neck carcinoma, melanoma, among others) that contain non-encapsulated, organized clusters of immune cell infiltrates (i.e. termed tertiary lymphoid structures (TLS) or ectopic lymphoid organs (ELO)) have significantly better clinical prognoses (superior overall survival, progression-free survival and/o responsiveness to chemotherapy) than comparable patients that lack such infiltrates. Notably, tumor-associated TLS have been suggested to serve as important sites of extranodal T cell priming, and to be characterized by mature (DC-LAMPhi+) DC deposits in intimate contact with recruited T cell populations around MECA-79+ (aka peripheral node addressin; PNAd, a marker of high endothelial venules/HEV in lymph nodes) blood vessels within the tumor microenvironment (TME). Similar results have been reported in murine solid cancer models in both wild-type and peripheral lymph node-deficient recipient animals. Nave lymphocytes have been identified in TLS within pulmonary lesions of patients with lung cancer, making it likely that these immune cells encounter their cognate antigen for the first time and develop into antigen-specific T effector cells within the TME (rather than in peripheral lymph nodes) in vivo. TLS featuring DC/Type-1 T cell clusters proximal to B cell nests have also been identified in human non-small-cell lung cancer (NSCLC) specimens, in association with improved long-term survival. B cells in NSCLC-associated TLS also appear to undergo all stages of their normal differentiation programming from nave precursors, including somatic hypermutation and Ig class-switching, development of plasma cells and production of (anti-tumor) antibodies. These data suggest the hypothesis that at under the appropriate conditions, tumors may be converted into functional lymphoid organs in which protective immunity may be effectively primed. Our proposal will employ informative wild-type, mutant and transgenic mouse models to determine the cellular and molecular mechanisms underlying Tbet- and IL-36/IL-36R-mediated therapeutic TLS development and induction of protective anti-tumor T cells capable of policing disseminated disease, and evaluate how the therapeutic benefits associated with the conversion of tumor sites into lymphoid organs can be further enhanced by cancer vaccines, adoptive cell therapies (ACT) and immune checkpoint blockade (ICB).

Public Health Relevance

Vaccine-induced immunity has classically been thought to involve immune programming events occurring in lymph nodes draining tissue sites of immunization. Our recent results in murine tumor models challenge this paradigm, and suggest instead, that the delivery of genetically-modified dendritic cells into the tumor microenvironment allows for tumors to acquire characteristics of lymph nodes in which therapeutic immunity may be developed, expanded and sustained in vivo, leading to superior anti-tumor benefit(s). The current proposal will determine mechanism(s) underlying the efficacy of such intervention strategies in order to define novel combination immunotherapy protocols that may ultimately be translated into clinic trials for the treatment of patients with cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA204419-04
Application #
9644518
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Sommers, Connie L
Project Start
2016-03-04
Project End
2021-02-28
Budget Start
2019-03-01
Budget End
2020-02-29
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Dermatology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Weinstein, Aliyah M; Giraldo, Nicolas A; Petitprez, Florent et al. (2018) Association of IL-36? with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer. Cancer Immunol Immunother :
Weinstein, Aliyah M; Chen, Lu; Brzana, Emily A et al. (2017) Tbet and IL-36? cooperate in therapeutic DC-mediated promotion of ectopic lymphoid organogenesis in the tumor microenvironment. Oncoimmunology 6:e1322238
Weinstein, Aliyah M; Storkus, Walter J (2016) Biosynthesis and Functional Significance of Peripheral Node Addressin in Cancer-Associated TLO. Front Immunol 7:301
Fecek, Ronald J; Storkus, Walter J (2016) Combination strategies to enhance the potency of monocyte-derived dendritic cell-based cancer vaccines. Immunotherapy 8:1205-18