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Review
. 2011 Apr;23(2):286-92.
doi: 10.1016/j.coi.2010.11.013. Epub 2010 Dec 23.

Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment

Thomas F Gajewski  1 , Mercedes Fuertes, Robbert Spaapen, Yan Zheng, Justin Kline
Affiliations
Review

Molecular profiling to identify relevant immune resistance mechanisms in the tumor microenvironment

Thomas F Gajewski et al. Curr Opin Immunol. 2011 Apr.

Abstract

The molecular identification of tumor antigens initially catalyzed substantial enthusiasm for the development of tumor antigen-based vaccines for the treatment of cancer. However, numerous vaccine approaches in melanoma and other cancers have yielded a low rate of clinical response, despite frequent induction of specific T cells as detected in the peripheral blood. This observation has prompted several investigators to begin interrogating the tumor microenvironment for biologic correlates to tumor response versus resistance. Evidence is beginning to emerge suggesting that distinct subsets of tumors may exist that reflect distinct categories of immune escape. Lack of chemokine-mediated trafficking, poor innate immune cell activation, and the presence of specific immune suppressive mechanisms can be found to characterize subsets of tumors. A non-inflamed tumor phenotype may predict for resistance to cancer vaccines, suggesting a possible predictive biomarker and patient enrichment strategy. But in addition, characterization of these subsets may pave the way for catering therapeutic interventions toward the biologic features of the tumor in individual patients.

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Figures

Figure 1
Figure 1
Two categories of tumor with distinct mechanisms of resistance to immune-mediated destruction at the effector phase. A. The non-inflamed tumors appear to have high expression of vascular markers as well as macrophages and fibroblasts. They have low indicators of innate inflammation, show poor chemokine production, and have a paucity of lymphocytes. It is hypothesized that the main reason for tumor escape in this subset is poor effector cell trafficking. B. The inflamed tumors appear to have a rich presence of innate immune signals, chemokines for T cell recruitment, and variable presence of T cells. However, these tumors also contain important immune suppressive mechanisms. It is hypothesized that the main reason for tumor escape in this subset is through dominant effects of negative regulation.
Figure 1
Figure 1
Two categories of tumor with distinct mechanisms of resistance to immune-mediated destruction at the effector phase. A. The non-inflamed tumors appear to have high expression of vascular markers as well as macrophages and fibroblasts. They have low indicators of innate inflammation, show poor chemokine production, and have a paucity of lymphocytes. It is hypothesized that the main reason for tumor escape in this subset is poor effector cell trafficking. B. The inflamed tumors appear to have a rich presence of innate immune signals, chemokines for T cell recruitment, and variable presence of T cells. However, these tumors also contain important immune suppressive mechanisms. It is hypothesized that the main reason for tumor escape in this subset is through dominant effects of negative regulation.
See this image and copyright information in PMC

References

    1. Gajewski TF, Meng Y, Harlin H. Chemokines expressed in melanoma metastases associated with T cell infiltration. Journal of Clinical Oncology, 2007 ASCO Annual Meeting Proceedings Part I. 2007;Vol 25:8501.
    1. Gajewski TF, Zha Y, Thurner B, Schuler G. Association of gene expression profile in melanoma and survival to a dendritic cell-based vaccine. J. Clin. Oncol. 2009;27:9002.
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    2. The above three reports, presented in abstract form at the ASCO annual meeting, represent the first data suggesting that gene expression profiling of the melanoma tumor microenvironment might be used to identify patients who may respond to melanoma vaccines.

    1. Gajewski TF, Louahed J, Brichard VG. Gene signature in melanoma associated with clinical activity: a potential clue to unlock cancer immunotherapy. Cancer J. 2010;16:399–403. - PubMed
    1. Harlin H, Meng Y, Peterson AC, Zha Y, Tretiakova M, Slingluff C, McKee M, Gajewski TF. Chemokine expression in melanoma metastases associated with CD8+ T-cell recruitment. Cancer Res. 2009;69:3077–3085. - PMC - PubMed

    2. This work was the first to demonstrate that a chemokine profile in the tumor microenvironment is associated with CD8+ T cell presence.