The oligometastatic spectrum in the era of improved detection and modern systemic therapy

Simple Summary Immune Checkpoint Inhibitors (ICIs) have demonstrated clinical efficacy in Microsatellite Instability High Colorectal Cancer (MSI-H CRC). However, in Microsatellite Stable (MSS) CRC, ICIs monotherapy provides limited clinical benefit. Therefore, efforts must be made to understand the highly heterogeneous CRC microenvironment and to find predictive biomarkers of response in order to adequately select CRC patients who may respond to ICIs-based therapies. Abstract Immune Checkpoint Inhibitors (ICIs) are well recognized as a major immune treatment modality for multiple types of solid cancers. However, for colorectal cancer (CRC), ICIs are only approved for the treatment of Mismatch-Repair-Deficient and Microsatellite Instability-High (dMMR/MSI-H) tumors. For the vast majority of CRC, that are not dMMR/MSI-H, ICIs alone provide limited to no clinical benefit. This discrepancy of response between CRC and other solid cancers suggests that CRC may be inherently resistant to ICIs alone. In translational research, efforts are underway to thoroughly characterize the immune microenvironment of CRC to better understand the mechanisms behind this resistance and to find new biomarkers of response. In the clinic, trials are being set up to study biomarkers along with treatments targeting newly discovered immune checkpoint molecules or treatments combining ICIs with other existing therapies to improve response in MSS CRC. In this review, we will focus on the characteristics of response and resistance to ICIs in CRC, and discuss promising biomarkers studied in recent clinical trials combining ICIs with other therapies.

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Biomarkers of Response and Resistance to Immunotherapy in Microsatellite Stable Colorectal Cancer: Toward a New Personalized Medicine

The multiple roles of LDH in cancer

Obstacles for T-lymphocytes in the tumour microenvironment: Therapeutic challenges, advances and opportunities beyond immune checkpoint

Clinical immunotherapy of solid tumors elicits durable responses only in a minority of patients, largely due to the highly immunosuppressive tumor microenvironment (TME). Although rational combinations of vaccine adjuvants with inflammatory cytokines or immune agonists that relieve immunosuppression represent an appealing therapeutic strategy against solid tumors, there are unavoidable nonspecific toxicities due to the pleiotropy of cytokines and undesired activation of off‐target cells. Herein, a Zn2+ doped layered double hydroxide (Zn‐LDH) based immunomodulating adjuvant, which not only relieves immunosuppression but also elicits robust antitumor immunity, is reported. Peritumorally injected Zn‐LDH sustainably neutralizes acidic TME and releases abundant Zn2+, promoting a pro‐inflammatory network composed of M1‐tumor‐associated macrophages, cytotoxic T cells, and natural‐killer cells. Moreover, the Zn‐LDH internalized by tumor cells effectively disrupts endo‐/lysosomes to block autophagy and induces mitochondrial damage, and the released Zn2+ activates the cGas‐STING signaling pathway to induce immunogenic cell death, which further promotes the release of tumor‐associated antigens to induce antigen‐specific cytotoxic T lymphocytes. Unprecedentedly, merely injection of Zn‐LDH adjuvant, without using any cytotoxic inflammatory cytokines or immune agonists, significantly inhibits the growth, recurrence, and metastasis of solid tumors in mice. This study provides a rational bottom‐up design of potent adjuvant for cancer metalloimmunotherapy against solid tumors.

A Peritumorally Injected Immunomodulating Adjuvant Elicits Robust and Safe Metalloimmunotherapy against Solid Tumors

Accumulating evidence suggests that a high tumour burden has a negative effect on anticancer immunity. The concept of tumour burden, simply defined as the total amount of cancer in the body, in contrast to molecular tumour burden, is often poorly understood by the wider medical community; nonetheless, a possible role exists in defining the optimal treatment strategy for many patients. Historically, tumour burden has been assessed using imaging. In particular, CT scans have been used to evaluate both the number and size of metastases as well as the number of organs involved. These methods are now often complemented by metabolic tumour burden, measured using the more recently developed 2-deoxy-2-[18F]-fluoro-d-glucose (FDG)-PET/CT. Serum-based biomarkers, such as lactate dehydrogenase, can also reflect tumour burden and are often also correlated with a poor response to immune-checkpoint inhibitors. Other circulating markers (such as circulating free tumour DNA and/or circulating tumour cells) are also attracting research interest as surrogate markers of tumour burden. In this Review, we summarize evidence supporting the utility of tumour burden as a biomarker to guide the use of immune-checkpoint inhibitors. We also describe data and provide perspective on the various tools used for tumour burden assessment, with a particular emphasis on future therapeutic strategies that might address the issue of inferior outcomes among patients with cancer with a high tumour burden. A high tumour burden has long been associated with inferior outcomes on traditional cancer therapies and emerging evidence suggests that tumour burden is particularly relevant for patients receiving immune-checkpoint inhibitors. Here, the authors summarize the available clinical and preclinical evidence for the role of tumour burden in determining the outcomes of patients receiving immune-checkpoint inhibitors and highlight areas that are likely to be of future research interest in this emerging area.

Camilo Garcia

Papers

Tumour burden and efficacy of immune-checkpoint inhibitors.