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Page 12 of 17 Spallanzani et al. J Cancer Metastasis Treat 2018;4:28 I http://dx.doi.org/10.20517/2394-4722.2018.31

Alternative approaches to enhance the immunotherapy efficacy in this subgroup of patients that are under
evaluation, include blockade of immunosuppressive chemokine signalling circuits and pathways or elimination
of MDSCs as observed in other neoplastic setting with immunosuppressive microenvironment [90,91] .

CONCLUSIONS AND FUTURE PERSPECTIVES
The development of immunotherapeutic agents has opened the way to a new era in the treatment of many
solid tumors, such as renal cell carcinoma, melanoma, bladder or non-small cell lung cancer. However,
despite tangible improvements in the prognosis of these malignancies, in most cases acquired resistance
finally develops and leads to significant clinical progression and death. Therefore, researchers have focused
primarily on the identification of the molecular bases that underlie the development of resistance in patients
treated with immunotherapy. Immune checkpoint inhibitors, such as anti-PD1 and anti-PD-L1, are the most
utilized among immunotherapeutic agents in the treatment of a broad spectrum of malignancies. In the
near future, uncovering the molecular mechanisms responsible for primary and acquired resistance to these
agents will certainly be of paramount importance. Firstly, it might allow a more accurate selection of patients
who are less suitable candidate to receive immunotherapy, thus leading to a more rational allocation of the
economic resources. As of today, basic research has focused primarily on PD-L1 expression as a potential
predictive biomarker of response to anti-PD1 and anti-PD-L1, but, in most of the cases, it is far away from
being defined a reliable biomarker. Secondly, by identifying the mechanisms underlying acquired resistance,
it might be possible to develop potential strategies to overcome them.

In the era of precision medicine, the recent consensus on molecular classification of CRC has paved the
way to a more personalized approach in the treatment of this disease, especially in the metastatic setting.
In particular, it is now established that patients with CMS1 subtypes CRC (mainly MSI-H) are the best
candidate for immunotherapy, with clinical trials demonstrating unprecedented results that lead to regulatory
approval of pembrolizumab and nivolumab. Nevertheless, some clinical challenges need to be addressed in
the near future in the treatment of MSI-H CRC. Firstly, as mentioned above, we need to understand why
some patients are primarily resistant to these drugs and the molecular mechanisms of the development of
secondary resistance. Secondly, it might be crucial to explore the role of immunotherapy in other settings,
such as in the prevention of CRC, in the conversion therapy of potentially resectable liver metastases, in the
adjuvant treatment of early-stage disease or in the neoadjuvant treatment of locally advanced rectal cancer.

However, MSI represents unfortunately an hallmark of a small fraction of patients with metastatic CRC.
Therefore, one of the major challenges that researchers need to face in the next few years is to define
strategies to convert immune-ignorant tumors (like CMS-2 and CMS-3 subgroups) into inflamed ones and
to restore a “CMS-1 like” immune microenvironment in CMS-4 tumors. Many clinical trials are ongoing
with new combination therapies. The results of these trials will hopefully help clinicians to abandon the
therapeutic paradigm of ‘one size fits all’ and allow a more selective biomarkers-driven approach.

Therefore, now that immunotherapy revolution has begun with a “new kid on the block” in the therapeutic
armamentarium of patients with CRC, enrollment in these clinical trials is largely encouraged.

DECLARATIONS
Authors’ contributions
Conceived and designed the manuscript: Spallanzani A, Gelsomino F, Caputo F, Santini C
Analysed and interpreted the data, drafted the article, revised it critically for important intellectual content
and finally approved the version to be submitted: all authors