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Comment
. 2015 Jan;5(1):16-8.
doi: 10.1158/2159-8290.CD-14-1397.

The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy

Yanping Xiao  1 , Gordon J Freeman  2
Affiliations
Comment

The microsatellite instable subset of colorectal cancer is a particularly good candidate for checkpoint blockade immunotherapy

Yanping Xiao et al. Cancer Discov. 2015 Jan.

Abstract

The microsatellite instable (MSI) subset of colorectal cancer exhibits an active Th1/CTL immune microenvironment, probably due to recognition of a high number of tumor neoantigens. However, the high expression of checkpoint molecules PD-1, PD-L1, CTLA-4, LAG-3, and IDO in MSI colorectal cancer distinguishes MSI from microsatellite stable colorectal cancer and creates an immunosuppressive microenvironment that may help MSI tumors evade immune destruction by the infiltrating immune cells. Though colorectal cancer does not have a good response rate to PD-1 pathway immunotherapy, these results suggest that the MSI subset of colorectal cancer is a particularly good candidate for checkpoint immunotherapy.

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Conflict of interest statement

Disclosure of Potential Conflicts of Interest

G.J. Freeman has patents and receives patent royalties on the PD-1 pathway from Bristol-Myers-Squibb, Merck, Roche, EMD-Serono, Boehringer-Ingelheim, Amplimmune, and Novartis. Y. Xiao is an inventor on a patent application for PD-L2 interaction with repulsive guidance molecule b which has been licensed to Novartis.

Figures

Figure 1
Figure 1
Immune microenvironment of MSI colorectal cancer. A. Deficits in DNA mismatch repair genes cause defective DNA mismatch repair, resulting in high levels of gene mutations manifested as MSI, which facilitate progression into an MSI CRC. Mutation-generated neoantigens are processed and presented on APCs and stimulate T cell activation, leading to an active Th1/CTL microenvironment; however, B. Upregulation of expression of checkpoint molecules such as PD-1, CTLA-4 and LAG-3 on T cells, PD-L1 on myeloid cells, and IDO expression in myeloid, APC, and tumor cells deliver inhibitory signals to suppress T cell activation, resulting in an immunosuppressive microenvironment. Green indicates activating and red inhibitory signals.
Figure 1
Figure 1
Immune microenvironment of MSI colorectal cancer. A. Deficits in DNA mismatch repair genes cause defective DNA mismatch repair, resulting in high levels of gene mutations manifested as MSI, which facilitate progression into an MSI CRC. Mutation-generated neoantigens are processed and presented on APCs and stimulate T cell activation, leading to an active Th1/CTL microenvironment; however, B. Upregulation of expression of checkpoint molecules such as PD-1, CTLA-4 and LAG-3 on T cells, PD-L1 on myeloid cells, and IDO expression in myeloid, APC, and tumor cells deliver inhibitory signals to suppress T cell activation, resulting in an immunosuppressive microenvironment. Green indicates activating and red inhibitory signals.
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Comment on

References

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