Differentiated state of initiating tumor cells is key to distinctive immune responses seen in H-RasG12V-induced squamous tumors

Michael A. Podolsky, Jacob T. Bailey, Andrew J. Gunderson, Carrie J. Oakes, Kyle Breech, Adam Bleier Glick

Research output: Contribution to journalArticle

Abstract

Heterogeneity in tumor immune responses is a poorly understood yet critical parameter for successful immunotherapy. In two doxycycline-inducible models where oncogenic H-RasG12V is targeted either to the epidermal basal/stem cell layer with a Keratin14-rtTA transgene (K14Ras), or committed progenitor/suprabasal cells with an Involucrin-tTA transgene (InvRas), we observed strikingly distinct tumor immune responses. On threshold doxycycline levels yielding similar Ras expression, tumor latency, and numbers, tumors from K14Ras mice had an immunosuppressed microenvironment, whereas InvRas tumors had a proinflammatory microenvironment. On a Rag1-/- background, InvRas mice developed fewer and smaller tumors that regressed over time, whereas K14Ras mice developed more tumors with shorter latency than Rag1+/+ controls. Adoptive transfer and depletion studies revealed that B-cell and CD4 T-cell cooperation was critical for tumor yield, lymphocyte polarization, and tumor immune phenotype in Rag1+/+ mice of both models. Coculture of tumorconditioned B cells with CD4 T cells implicated direct contact for Th1 and regulatory T cell (Treg) polarization, and CD40-CD40L for Th1, Th2, and Treg generation, a response not observed from splenic B cells. Anti-CD40L caused regression of InvRas tumors but enhanced growth in K14Ras, whereas a CD40 agonist mAb had opposite effects in each tumor model. These data show that position of tumor-initiating cells within a stratified squamous epithelial tissue provokes distinct B- and CD4 T-cell interactions, which establish unique tumor microenvironments that regulate tumor development and response to immunotherapy.

Original languageEnglish (US)
Pages (from-to)198-210
Number of pages13
JournalCancer Immunology Research
Volume5
Issue number3
DOIs
StatePublished - Mar 1 2017

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Neoplastic Stem Cells
Neoplasms
Transgenes
CD40 Ligand
B-Lymphocytes
Doxycycline
T-Lymphocytes
Immunotherapy
Stem Cells
Tumor Microenvironment
Adoptive Transfer
Regulatory T-Lymphocytes
Coculture Techniques
Cell Communication
Epithelium
Lymphocytes

All Science Journal Classification (ASJC) codes

  • Immunology
  • Cancer Research

Cite this

Podolsky, Michael A. ; Bailey, Jacob T. ; Gunderson, Andrew J. ; Oakes, Carrie J. ; Breech, Kyle ; Glick, Adam Bleier. / Differentiated state of initiating tumor cells is key to distinctive immune responses seen in H-RasG12V-induced squamous tumors. In: Cancer Immunology Research. 2017 ; Vol. 5, No. 3. pp. 198-210.
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Differentiated state of initiating tumor cells is key to distinctive immune responses seen in H-RasG12V-induced squamous tumors. / Podolsky, Michael A.; Bailey, Jacob T.; Gunderson, Andrew J.; Oakes, Carrie J.; Breech, Kyle; Glick, Adam Bleier.

In: Cancer Immunology Research, Vol. 5, No. 3, 01.03.2017, p. 198-210.

Research output: Contribution to journalArticle

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