Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients: Beyond the Abstract

The overall survival of patients with non-operable metastasized colorectal cancer (CRC) is despite all improvements in surgical and medical treatments about 24 months.[1] With advanced metastatic stage only few treatment options remain for patients. The mainstay therapies are chemotherapies (either oxaliplatinum or irinotecan based and 5-FU derivatives). Immunotherapeutic approaches have been fairly unsuccessful so far for the vast majority of patients with CRC. Microsatellite stable colorectal tumors do not respond to current immunotherapies.[2] These immunotherapies are aimed at strengthening the acquired immune response, specifically activating T-cells against the tumor cells via inhibition of the PD-1/PD-L1 axis.  

To better understand the local microenvironment and the underlying heterogeneity[3] in colorectal cancer metastases, an in depth profiling of CRC liver metastases was performed.[4-6] Utilizing automated whole slide cell quantification and multiplex proteomics allowed to identify distinct regions (or compartments) within the tissue, forming a specific immunological microenvironment. In contrast to the published data on the CRC primary tumor[7], the metastatic site does not contain a typical TH1, TH2 or TH17 profile of cytokines and cells.  Instead, two subsets of myeloid cells produce a gradient of chemokines that drives T cells to the invasive margin and not into the inner part of the metastasis. The signal protein CCL5, which is normally involved in inflammatory process regulation as it leads to migration of immune cells into the affected tissue, is produced only by T cells. CCL5 is associated also with tumor-promoting effects in breast cancer metastases and so the observed effects in CRC cell lines showed similar results. The lymphocytes in the microenvironment are thereby promoting tumor cells and no signs of anti-tumoral activation were observed. IN this situation, the analysis of the main receptor for CCL5 showed a clear picture. CCR5 was found on all tumor cells and also on macrophages and lymphocytes. The CCR5 receptor is already well characterized from the field of infectiology, because the human immunodeficiency (HI) virus also binds to CCR5 and penetrates the cells this way. An already registered drug blocks the surface protein CCR5 and is used therapeutically for HIV patients. With this drug, a specific CCR5 inhibitor, experiments in a new fully human model system were performed. This so called human explant model system allowed to manipulate the complete set of human cells from the microenvironment in CRC liver metastases. Specific CCR5 inhibition reversed the tumor-promoting effects and led to selective tumor cell death. Further experiments revealed the key component of the anti-tumoral effect: macrophages. Macrophages in the in tumor microenvironment were re-activated against the tumor, with this re-polarization leading to anti-tumoral effects mediated by interferons and reactive oxygen species. No new influx of myeloid cells was necessary for the selected induction of tumor cell death. The re-polarized macrophages were generated out of the existing pool of myeloid cells within the microenvironment, leading to a reconfiguration of the innate immune cell composition.

Following the pre-clinical experiments, a phase-I trial involving 14 patients was initiated and the serial biopsies from the human patients confirmed the preclinical data from the human explant model system.  So the prospective clinical trial could confirm the selective tumor cell death inducing effect of the re-polarized macrophages. Specific changes in signaling pathways, i.e. via STAT3, indicated an activation of an antiviral program in macrophages. Besides the effect on the tissue level, objective clinical responses were seen. Especially in the combination therapy with previously ineffective chemotherapies, patients showed objective responses.  Toxicities were generally mild (87% grade I and II adverse events) and could be managed in an outpatient setting.[8] 

In summary, the findings indicate a role for macrophage re-polarization therapy in colorectal cancer and further clinical developments are warranted. The control of the macrophage polarization through the specific factors in the local microenvironment is an interesting therapeutical option. Identification of these specific factors in other cancer entities is ongoing. The MARACON trial for the first time successfully utilized re-polarized macrophages via CCR5 inhibition. Combinatorial approaches with activation of the innate and the adaptive arm of the immune system are promising. In addition, the human explant model system was validated in the prospective trial as well and therefore this new alternative models has the potential to improve clinical developments also for other diseases. 

Written by:
Meggy Suarez-Carmona and Niels Halama, National Center for Tumor Diseases, Department of Medical Oncology, Internal Medicine VI, University Hospital Heidelberg, Germany. 


References:
1. Van Cutsem E, Cervantes A, Nordlinger B, Arnold D, Group EGW (2014) Metastatic colorectal cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals of oncology : official journal of the European Society for Medical Oncology / ESMO. 25 Suppl 3: iii1-9. doi: 10.1093/annonc/mdu260

2. Le DT, Uram JN, Wang H et al. (2015) PD-1 Blockade in Tumors with Mismatch-Repair Deficiency. N. Engl. J. Med. 372: 2509-20. doi: 10.1056/NEJMoa1500596

3. Kahlert C, Gaitzsch E, Steinert G et al. (2012) Expression analysis of aldehyde dehydrogenase 1A1 (ALDH1A1) in colon and rectal cancer in association with prognosis and response to chemotherapy. Ann. Surg. Oncol. 19: 4193-201. 

4. Halama N, Zoernig I, Spille A et al. (2010) Quantification of prognostic immune cell markers in colorectal cancer using whole slide imaging tumor maps. Anal. Quant. Cytol. Histol. 32: 333-40. 

5. Halama N, Michel S, Kloor M et al. (2011) Localization and density of immune cells in the invasive margin of human colorectal cancer liver metastases are prognostic for response to chemotherapy. Cancer Res. 71: 5670-7. doi: 10.1158/0008-5472.CAN-11-0268

6. Halama N, Braun M, Kahlert C et al. (2011) Natural killer cells are scarce in colorectal carcinoma tissue despite high levels of chemokines and cytokines. Clinical cancer research : an official journal of the American Association for Cancer Research. 17: 678-89. doi: 10.1158/1078-0432.CCR-10-2173

7. Galon J, Costes A, Sanchez-Cabo F et al. (2006) Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313: 1960-4. 

8. Halama N, Zoernig I, Berthel A et al. (2016) Tumoral Immune Cell Exploitation in Colorectal Cancer Metastases Can Be Targeted Effectively by Anti-CCR5 Therapy in Cancer Patients. Cancer Cell. 29: 587-601. doi: 10.1016/j.ccell.2016.03.005