Tumor cell-intrinsic factors underlie heterogeneity of immune cell infiltration and response to immunotherapy

By Jinyang Li, Katelyn T. Byrne, Fangxue Yan, Taiji Yamazoe, Zeyu Chen, T. Baslan, Lee P. Richman, Jeffrey H. Lin, Yu H. Sun, A. Rech and 19 more. Immunity, 2018

620 citations recorded by the source corpus.

Summary The biological and functional heterogeneity between tumors—both across and within cancer types—poses a challenge for immunotherapy. To understand the factors underlying tumor immune heterogeneity and immunotherapy sensitivity, we established a library of congenic tumor cell clones from an autochthonous mouse model of pancreatic adenocarcinoma. These clones generated tumors that recapitulated T cell‐inflamed and non‐T‐cell‐inflamed tumor microenvironments upon implantation in immunocompetent mice, with distinct patterns of infiltration by immune cell subsets. Co‐injecting tumor cell clones revealed the non‐T‐cell‐inflamed phenotype is dominant and that both quantitative and qualitative features of intratumoral CD8+ T cells determine response to therapy. Transcriptomic and epigenetic analyses revealed tumor‐cell‐intrinsic production of the chemokine CXCL1 as a determinant of the non‐T‐cell‐inflamed microenvironment, and ablation of CXCL1 promoted T cell infiltration and sensitivity to a combination immunotherapy regimen. Thus, tumor cell‐intrinsic factors shape the tumor immune microenvironment and influence the outcome of immunotherapy. Graphical Abstract Figure. No caption available. HighlightsGenerated a library of congenic pancreatic cancer cell clones derived from KPC miceEach tumor elicited unique immune infiltration correlating with therapeutic responseTumors lacking T cells exhibit different epigenetic and transcriptomic statusCXCL1 was increased in therapy‐resistant tumors that lacked T cell infiltration &NA; Using a library of pancreatic cancer cell clones, Li et al. identify heterogeneous and multifactorial pathways regulating tumor‐cell‐intrinsic mechanisms that dictate the immune microenvironment and thereby responses to immunotherapy. This tumor clone library provides a tool for identifying new targets responsible for thwarting responses to immunotherapy in resistant tumors.

Subfields: Immunology, Oncology

View Paper: https://www.semanticscholar.org/paper/fc1302843f29a243b54a354643d6e51e8ad16ef7

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Immunology

In Oncology

Citations in the corpus

IL-1-induced JAK/STAT signaling is antagonized by TGF-β to shape CAF heterogeneity in pancreatic ductal adenocarcinoma. (2018, background): “The secretory phenotype of iCAFs suggest a role for this CAF subtype in promoting tumor progression, chemoresistance and other cancer-associated systemic effects, such as cachexia and immune suppression (6,9,11,21-24,38,45,46).”
Autophagy promotes immune evasion of pancreatic cancer by degrading MHC-I (2020, positive): “We also find that mice deficient for CD103 + dendritic cells (DCs; Batf3 −/− ) 21 , which play pivotal roles in CD8 + T-cell priming 22 and recruitment into tumours 20,23 , showed almost complete loss of tumour-infiltrating CD8 + T cells (Fig.”
Cooperation between Constitutive and Inducible Chemokines Enables T-cell Engraftment and Immune Attack in Solid Tumors (2019, background): “Most tumors shape local chemokine networks to promote their growth by recruiting stromal cells like tumor-associated macrophages (TAMs) (Viola et al., 2012), myeloid-derived suppressor cells (MDSC) (Li et al., 2018), and regulatory T cells (Treg) (Curiel et al., 2004; Facciabene et al., 2011), all a”
The Tumor Microenvironment: A Milieu Hindering and Obstructing Antitumor Immune Responses (2020, background): “The preconditioning consisted of cyclophosphamide and fludarabine given a few days prior to infusion of ex vivo-stimulated TILs to reduce regulatory T cells.”