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but also with 164/5702 (2.9%) MSS cases having also TMB high status. Authors were able to confirm
the activity of an anti-PD1 inhibitor in patients having TMB high status, thus suggesting that screening
patients on the basis of MSI-H status positivity is somehow restricting the number of patients that could
ultimately benefit from anti-PD1/PDL-1 treatment.

These data suggest that, at least in the foreseeable future, more data are needed to further assess the clinical
impact of these treatment approaches in everyday practice, as there are a few crucial topics still to be
addressed (namely the fitness of T cells, how to increase sensitivity of the TME towards T cell mediated
killing and the selection of patients that benefit best from these treatment approaches).

CONCLUSION
In the past few years, introduction of new therapeutic approaches and better selection of patients have
significantly changed treatment strategy of CRC and definitely improved patient outcome.

Immunotherapy has been the most important revolution in cancer treatment of recent years and it continues
to show impressive results in lethal malignancies such as melanoma or lung cancer. Still, results observed
in CRC with checkpoint inhibitors immunotherapy are modest if compared to other tumor entities and
limited to a small subset of patients with MSI. In this context, a better knowledge of tumor immune
microenvironment is essential to developing effective therapeutic strategies and overcoming resistance.

Interestingly, molecular characterization of CRC has shown that CMSs are associated with specific
immune infiltration profiles corresponding with characteristic mechanisms of immune escape.

In particular, CMS1 subtype presents the most favourable situation for immunotherapy efficacy with
high immune infiltration rich in Th1 cells and TILs, explaining the efficacy of checkpoint inhibitors in
this subtype. CMS4 also presents high immune infiltrate but with an unfavourable, inflamed molecular
orientation characterized by intratumoral MDSC, M2-macrophages and B-cells associated with pro-
inflammatory gene expression, including myeloid chemokines, immune suppressive molecules and
complement factors. In this situation, the combination of checkpoint inhibitors with TGF pathway
inhibition represents a promising strategy as well as the use of angiogenesis inhibitors or anti-MDSCs
treatment. On the contrary, CMS2 and CMS3 are poorly immunogenic tumors with scarce immune
infiltrate. In this context, combination of checkpoint inhibitors with MEK-inhibition or anti-EGFR
monoclonal antibodies could allow to overcome resistance. In addition, monoclonal antibodies targeting
tumor-associated antigens, such as CEA, engineered with IL-2 may be able to increase immune infiltration
and activates NK and T cells also in tumors with poor immune infiltration. Other strategies which may be
effective in the setting of CMS2 and CMS3 are the combination of chemotherapy and immune checkpoint
inhibitors or passive immunotherapy treatments as cancer vaccines with primed DCs.

In conclusion, the development of new effective immunotherapeutic strategies in CRC should be driven by
a better knowledge of mechanisms of resistance to current treatments and take in account differences in
immune microenvironment between different molecular subtypes to find the best treatment for each patient.

DECLARATIONS
Authors’ contributions
Responsible for the paper: Berardi R
Concept, design, definition of intellectual content: Bittoni A
Literature search: Meletani T, Sotte V, Cantini L
Manuscript preparation: Meletani T, Sotte V, Cantini L, Giampieri R