• COLORECTAL CANCER
• IMMUNOTHERAPY
• MACROPHAGES

Unlike in numerous other tumors, the efficacy of checkpoint inhibitor-based immunotherapies in colorectal cancer (CRC) is restricted to the small subgroup of patients with mismatch repair-deficiency or microsatellite instability accounting for only a small minority of cases.1 The vast majority of patients with advanced, microsatellite-stable CRC, however, is currently resistant to checkpoint inhibitors and thus are not candidates for regimens containing antibodies targeting inhibitory immune checkpoint receptors. Therefore, it is an urgent unmet clinical need to explore new avenues to render microsatellite-stable CRCs immunologically ‘hot’ and thus susceptible to checkpoint inhibitor-based therapies.

In many cancers including CRC, resistance to immunotherapy is mainly mediated by the tumour immune microenvironment. Particularly, infiltrating immune cells such as tumour-associated macrophages (TAMs) can polarise into a tumour-promoting, anti-inflammatory M2 phenotype that mediates T cell exhaustion thus rendering the tumour immunologically ‘cold’.2 To date, it remains largely unresolved how to effectively reverse T cell exhaustion in these tumours. Given the intense immunosuppressive impact of M2-polarised TAM on T cells, signalling pathways in M2-TAMs represent an interesting avenue to indirectly enhance T cell function.2

In this context, in GUT, Li et al 3 identified a promising myeloid signalling target: The membrane spanning four domains A4A (MS4A4A) protein that has been previously described as marker for M2 macrophages being highly expressed in TAMs.3 4 As demonstrated in previous studies, high MS4A4A expression is significantly associated with poor prognosis in several cancers3 5 but its functional relevance is largely unknown so far. Mechanistically, the authors could show that MS4A4A promotes M2 polarisation of macrophages by activating both PI3K/AKT and JAK/STAT6 pathways. Interestingly, it could be shown that the PI3Kγ isoform was predominantly instrumental in mediating MS4A4A-dependent effects in macrophage polarisation. There is accumulating evidence in various tumour models that PI3Kγ acts as crucial signalling node in TAMs whose inhibition diminishes M2 polarisation and thereby enhances T cell cytotoxicity.6 The exact molecular mechanisms, however, involved in downstream signalling between the membrane protein MS4A4A and PI3K/AKT and JAK/STAT6 remain to be fully elucidated.

Using murine subcutaneous and orthotopic tumour models, the authors could further show that inhibition of MS4A4A by a newly developed anti-MS4A4A mAb decreased tumour growth and improved the effect of checkpoint inhibitor therapy.3 When combined with radiotherapy, MS4A4A blockade together with checkpoint inhibition was effective even in large, treatment resistant tumours. As expected, this antitumoural effect was accompanied by reduced infiltration of M2-TAMs and exhausted T cells, and by increased infiltration of effector CD8+cytotoxic T cells (figure 1).

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Figure 1

Schematic depiction of the molecular mechanisms of MS4A4A targeting on immunogenic tumour cell death. CPI, checkpoint inhibitor.

Interestingly and somewhat contradictory to the results by Li et al, a recent paper by Mattiola et al could show that MS4A4A colocalises with Dectin-1 in the lipid rafts and MS4A4A-deficient macrophages are impaired in their ability to support Dectin-1-dependent cross-talk with NK cells in various preclinical tumour models, suggesting that MS4A4A deficiency in macrophages compromises Dectin-1-driven NK cell-mediated resistance to metastasis.7 Therefore, the functional impact of MS4A4A on different immune populations and growth of different tumour entities remains to be further elucidated.

Numerous approaches are currently being evaluated to target immunosuppressive TAMs in cancers, thereby aiming to unleash cytotoxic T cell response. In principle, TAMs can be depleted or their recruitment to the tumours can be inhibited, for example, by blocking the CSF1-CSF1R axis to induce TAM apoptosis or by inhibiting the CCL2-CCR2 axis to decrease TAM recruitment to the tumour site. However, these rather unselective approaches may also affect the immunostimulatory, antitumoural role of macrophages as antigen-presenting cells in solid tumours.3 Therefore, reprogramming or repolarising immunosuppressive TAMs into immunostimulatory TAMs is an attractive research direction which is currently being explored, among them reprogramming TAMs with CD40 agonists to restore antitumour immunity.3 In this context, the anti-MS4A4A treatment introduced by Li et al provides a new therapeutic avenue to target myeloid signalling in solid cancers.3

Several preclinical studies and clinical trials currently explore the combination of myeloid targeting together with simultaneous or subsequent checkpoint inhibition. In this context, in mouse models of CRC, treatment with a humanised antibody binding to CSF1R led to reduced TAM infiltration and increased CD8+T cell infiltration.8 9 Clinical trials examining the combination of anti-CSF1R and anti-PD-L1 in advanced cancers including CRC are ongoing (eg, NCT NCT02777710).

It remains to be elucidated if the therapeutic benefit of targeting murine MS4A4A also translates into a clinical benefit in human trials. With the advent of single-cell omics, the polarisation profiles of TAMs turn out to be much more differentiated than previously anticipated in the M1/M2 categorisation system.2 Human correlative data presented by Li et al demonstrate an inverse correlation between MS4A4A expression and poor outcome in several cancer types. This suggests that MS4A4A could also play an important role as modulator of immunogenicity in human cancers.

In this context, the fact that anti-MS4A4A targeted therapy did not induce significant toxicity in mice indicates that this therapeutic avenue might be safe also in human cancer treatment. Given the significant differences between human and murine immune response,10 however, clinical trials are warranted to evaluate the systemic toxicity and the specificity of MS4A4A-directed antibodies in the humans. Given the high expression selectivity in myeloid cells, MS4A4A represents a highly interesting new avenue to explore as therapeutic target for modulating the protumoural macrophage populations in order to enhance the immunogenicity of solid cancers including CRC and their susceptibility to checkpoint inhibitor therapies.