Gutting it Out: Developing Effective Immunotherapies for Patients With Colorectal Cancer

Abstract

Risk factors for colorectal cancer (CRC) include proinflammatory diets, sedentary habits, and obesity, in addition to genetic syndromes that predispose individuals to this disease. Current treatment relies on surgical excision and cytotoxic chemotherapies. There has been a renewed interest in immunotherapy as a treatment option for CRC given the success in melanoma and microsatellite instable (MSI) CRC. Immunotherapy with checkpoint inhibitors only plays a role in the 4%–6% of patients with MSIhigh tumors and even within this subpopulation, response rates can vary from 30% to 50%. Most patients with CRC do not respond to this modality of treatment, even though colorectal tumors are frequently infiltrated with T cells. Tumor cells limit apoptosis and survive following intensive chemotherapy leading to drug resistance and induction of autophagy. Pharmacological or molecular inhibition of autophagy improves the efficacy of cytotoxic chemotherapy in murine models. The microbiome clearly plays an etiologic role, in some or most colon tumors, realized by elegant findings in murine models and now investigated in human clinical trials. Recent results have suggested that cancer vaccines may be beneficial, perhaps best as preventive strategies. The search for therapies that can be combined with current approaches to increase their efficacy, and new knowledge of the biology of CRC are pivotal to improve the care of patients suffering from this disease. Here, we review the basic immunobiology of CRC, current “state-of-the-art” immunotherapies and define those areas with greatest therapeutic promise for the future.

Microsatellite Instability and Immune Response: From Microenvironment Features to Therapeutic Actionability—Lessons from Colorectal Cancer

“…However, neoplastic cells with dMMR eventually will overexpress several immune checkpoint (IC) proteins, such as PD-1 e PD-L1, which act to restrain the efficiency of the cytotoxic immune response. The pharmacological inhibition of these ICs through immunotherapy (such as Pembrolizumab and Nivolumab) allows for overcoming such blockade of the immune response, restoring an active adaptive response toward cancer cells [ 23 , 24 , 25 ].…”

Colorectal cancer vaccines: The current scenario and future prospects

“…Additionally, activated B cells promote tumor killing effects through antibody-dependent cellular cytotoxicity (ADCC) ( 12 ). In turn, stressed tumor cells release vast numbers of antigens and damage-associated molecular patterns (DAMPs) that are captured, processed, and presented by APCs to induce polyclonal T-cell responses, thereby multiplying antitumor immune responses ( 13 ). Overall, cancer vaccines contribute to tipping the balance from tolerance toward active immunity against tumor cells, rendering the cancer immunity cycle functional.…”