Page 13 - Read Online
P. 13

Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31                     Page 7 of 17


                                     Hot tumors                                 Cold tumors




                        CMS1: Immune         CMS4: Mesenchymal     CMS2: Canonical      CMS3: Metabolic


                        Hypermutation           Inflammation    WNT and MYC activation  KRAS mutations
                           dMMR               Stromal infiltration
                        BRAF mutations          Angiogenesis

                                 TILs
                                NK cells                TILs
                              Macrophages               CAFs               Poor immunogenicity


                        Cancer           PD1   Cancer         TGFβ
                         cells   ↑↑ CTLA4       cells     complement
                                        IDO1

                               CXCR3/CCR5                CCL2
                                  IFNγ                  CXCL12
                             Immunotherapy    CHT + target therapy + immunotherapy?

               Figure 1. Immune subtypes classification. CMS: Consensus molecular subytpe; dMMR: deficit mismatch repair; TILs: tumor-infiltrating
               lymphocytes; PD1: programmed death protein 1; CTLA4: cytotoxic T-lymphocyte-associated protein 4; IDO1: indoleamine-pyrrole
               2,3-dioxygenase; IFNg: interferon gamma; CXCR3-CCR5: chemokine receptor type 3-5; CAFs: cancer associated fibroblasts; TGFβ:
               transforming growth factor beta; CCL2-CXCL12: chemokin ligand 2-12

               TGF-B signalling and an angiogenic microenvironment should be targeted to restore a “CMS-1-like”
               immune microenvironment. Preclinical data suggested a synergic effect of TGF-B and PD-1 inhibition in
                                              [48]
               mouse model of mesenchymal CRC . The role of chemotherapy alone in CMS4 tumours is ambiguous:
               chemotherapy has a detrimental effect on the immune system but the cell-necrosis inducted and the
               subsequent release of neo antigens should be immunogenic, promoting the activity of APC and thus
               an immune-response. Based on previous clinical data suggesting an adjuvant immune effect of anti-
               VEGF antibody combined with standard chemotherapy, the combination of FOLFOX, bevacizumab and
               atezolizumab has been evaluated in a cohort of 23 naïve patients. Almost all patients demonstrated clinical
               benefit with 11 (48%) achieving partial response and 9 (40%) stable disease: how these results should be
               interpreted is still unclear but the clinical benefit reached in almost 90% of patients deserves further
               investigations [49,50] . Several other clinical trials investigating the combination of chemotherapy, bevacizumab
               and check-point inhibitors are ongoing.

               CMS2 and CMS3 tumours are typically “cold tumours” with downregulation of MHC class I and lack
                                    [47]
               immune cell infiltration . A lot of strategies are still under evaluation to convert these immune-ignorant
               tumours into “hot tumours”.

               In preclinical experiences, MEK and PD-1 co-inhibition showed a synergistic effect in colorectal, melanoma
                                    [51]
               and breast cancer models . Cobimetinib, a MAPK inhibitor, upregulates IFN-gamma, HLA molecules and
                                                                                      [52]
               PDL-1 expression stimulating CD8+ CTLs activity in the tumour microenvironment .
               Based upon these preclinical data, a phase I study that combined MEK and PDL-1 inhibition (cobimetinib
               and atezolizumab) was designed in which 4 of the 23 patients enrolled achieved partial response(17%): 3
                                                                           [53]
               of these 4 patients were pMMR, 1 had an unknown MSI/MMR status . Actually, a three arms phase III
               study in which patients with pMMR chemo-refractory CRC are randomized to receive atezolizumab, or a
   8   9   10   11   12   13   14   15   16   17   18