Introduction: Immunotherapies have entered routine practice in a number of tumor types, harnessing adaptive immune responses with good effect. Checkpoint blockade including anti-PD-1 therapy is effective in immunogenic tumor types such as melanoma and microsatellite unstable colorectal cancer. Presence of T cell infiltrates, expression of checkpoint molecules (PD-1, PD-L1) and MHC-1 are proposed measures of an immune-active microenvironment potentially predictive of response to immunotherapy. Most CRCs exhibit an immunosuppressive tumor microenvironment, thought to preclude use of such therapies. It is possible strategies to enhance immunogenicity in MMR proficient CRC may enable a broader use of immunotherapy in CRC. This pilot study evaluates whether treatment with FOLFOX chemotherapy can enhance tumor immune responses in pMMR locally advanced rectal cancer (LARC).
Methods: Patients with LARC receiving neoadjuvant therapy were prospectively studied. In our institution, neoadjuvant treatment comprises FOLFOX chemotherapy for 8 cycles followed by chemoradiation. Biopsies were performed prior to and following 4 cycles of FOLFOX chemotherapy. Immunohistochemistry was performed on matched samples to grade T cell (CD3+, CD8+, CD45RO+), T regulatory cells (FOXP3+) and macrophages (CD163+). We also evaluated MHC1 and PD-1/ PDL-1 expression. Infiltrates were scored as Hi/Lo in the stromal and epithelial compartments based on cell counts. MHC-1 expression was evaluated with the modified histoscore. PD-1/ PDL-1 positivity was considered present when clusters of ≥10 positive cells were seen. Depending on changes in absolute cell counts or antibody intensity, alterations in immune responses were considered to increase, decrease or remain unchanged after treatment. Treatment response at end of therapy was graded by radiological/ pathological assessments as Excellent/Good/Poor.
Results: Eight patients treated were evaluated for whom matched biospies before and after 4 cycles of induction FOLFOX chemotherapy were available (6 males and 2 females, ages 32-75yrs). All had clinical Stage III disease (2 were cT4 tumors, 5 were cT3 and 1 was cT2). 3 tumors were at ≤5cm, 3 tumors were between 5-10cm and 2 were >10cm from the anal verge. Pretreatment MMR status was available in 7 patients all of which had retained expression of MMR proteins. 5 patients had an excellent response, 1 had a good response and 2 had poor responses. Pre-treatment patterns of immune infiltrates were mixed and did not correlate with response. Of note, the 2 tumors with a poor response exhibited low levels of both stromal/epithelial CD3+ and CD8+ cells. Tumor immune responses increased with chemotherapy in the majority. CD3 cell counts increased in 6/8 patients, CD8 and CD45RO counts increased in 5/8 patients and FOXP3 Tregs were increased in 3 and unaffected/reduced in 4. CD163 counts were increased in 4/8. MHC1 expression was increased in 6/8 patients. PDL1 positivity was increased after FOLFOX in 6/8 and PDL-1 positivity increased in 4/8. There were no appreciable patterns of immune responses correlating with treatment response.
Conclusion: Within the confines of this small pilot study, FOLFOX chemotherapy was associated with enhanced tumor immune responses in LARC without an obvious relationship with treatment response. Importantly, increased T cell infiltrates, MHC-1 expression and increased PD-1 positivity were seen. These results require further validation but provide initial evidence to suggest neoadjuvant chemotherapy results in a more immune-active tumor microenvironment and could potentially be utilized to prime immune responses prior to immunomodulatory treatments.
Citation Format: Campbell S. Roxburgh, Jinru Shia, Efsevia Vakiani, Tanisha Daniel, Martin R. Weiser. An investigation into potential immune priming of the tumor microenvironment with FOLFOX chemotherapy in locally advanced rectal cancer [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr A122.
- ©2016 American Association for Cancer Research.