MHC Intratumoral Heterogeneity May Predict Cancer Progression and Response to Immunotherapy.

Irene Romero,Cristina Garrido,Federico Garrido,Virginia Chamorro,Angel M Garcia-Lora,Antonia Collado,Ignacio Algarra

doi:10.3389/fimmu.2018.00102

Abstract

An individual tumor can present intratumoral phenotypic heterogeneity, containing tumor cells with different phenotypes that do not present irreversible genetic alterations. We have developed a mouse cancer model, named GR9, derived from a methylcholanthrene-induced fibrosarcoma that was adapted to tissue culture and cloned into different tumor cell lines. The clones showed diverse MHC-I phenotypes, ranging from highly positive to weakly positive MHC-I expression. These MHC-I alterations are due to reversible molecular mechanisms, because surface MHC-I could be recovered by IFN-γ treatment. Cell clones with high MHC-I expression demonstrated low local oncogenicity and high spontaneous metastatic capacity, whereas MHC-I-low clones showed high local oncogenicity and no spontaneous metastatic capacity. Although MHC-I-low clones did not metastasize, they produced MHC-I-positive dormant micrometastases controlled by the host immune system, i.e., in a state of immunodormancy. The metastatic capacity of each clone was directly correlated with the host T-cell subpopulations; thus, a strong decrease in cytotoxic and helper T lymphocytes was observed in mice with numerous metastases derived from MHC-I positive tumor clones but a strong increase was observed in those with dormant micrometastases. Immunotherapy was administered to the hosts after excision of the primary tumor, producing a recovery in their immune status and leading to the complete eradication of overt spontaneous metastases or their decrease. According to these findings, the combination of MHC-I surface expression in primary tumor and metastases with host T-cell subsets may be a decisive indicator of the clinical outcome and response to immunotherapy in metastatic disease, allowing the identification of responders to this approach.

Highlights

It is widely accepted that tumors can display intratumoral genetic heterogeneity, and attention has recently focused on its implications for clinical outcomes, metastatic progression, and the response to different therapies [1,2,3,4]
The present results indicate that intratumoral heterogeneity in the MHC-I cell surface expression (MHC-I phenotype) of a tumor may determine its oncogenic potential, metastatic capacity, and response to immunotherapy (Figure 6)
Cell clones isolated from a MCA-induced primary fibrosarcoma in BALB/c mice had a wide range of MHC-I phenotypes, from negative to highly positive

Summary

Introduction

It is widely accepted that tumors can display intratumoral genetic heterogeneity, and attention has recently focused on its implications for clinical outcomes, metastatic progression, and the response to different therapies [1,2,3,4]. The clinical practice of ordering a single biopsy from a progressing tumor may not be adequate to assess intratumoral complexity and, importantly, may provide an incomplete view of potential therapeutic targets. Intratumoral heterogeneity involves genetic alterations and epigenetic mechanisms and/or differences in protein expression levels in response to microenvironment signals or posttranscriptional modifications. Immunoediting removes the more immunogenic tumor cells in a primary tumor, whereas different immune escape mechanisms are developed by less immunogenic cells [7]. One well-documented method by which tumor cells avoid immune surveillance is MHC-I downregulation, which renders tumor cells invisible to T-cellmediated cytotoxicity (immunoblindness) [8,9,10]

Methods

Results

Conclusion