Anti-L-selectin monoclonal antibody treatment in mice enhances tumor growth by preventing CTL sensitization in peripheral lymph nodes draining the tumor area

To examine the in vivo contribution of L-selectin in the sensitization of tumor-specific CTL, we investigated the effects of treatment with the anti-L-selectin monoclonal antibody (MAb) MEL-14 on the immune response to Moloney-murine sarcoma virus (M-MSV)-induced tumors, which exhibit spontaneous regression following generation of a strong virus-specific CTL response. Daily systemic administration of MEL-14 for 10 days to M-MSV-injected mice gave rise to larger sarcomas that persisted for a longer time, compared with those arising in control mice injected with virus only. The enhanced tumor growth could not be attributed to cytotoxic activity on leukocytes by MEL-14 since no reduction in the total cell number was detected in peripheral blood and spleen of MAb-treated mice. Evaluation of the immunological response in MAb-treated animals revealed a strong reduction in the generation of virus-specific CTL precursors (CTLp) in tumor-draining peripheral lymph nodes (PLN) 10 and 15 days after M-MSV injection, while in spleen, where lymphocyte localization is independent of L-selectin expression, CTLp generation was only delayed. By day 20, when tumors had begun to regress, the CTLp number showed a marked increase in both spleen and local PLN, where naive recirculating CTL could now enter because L-selectin was no longer down-regulated or blocked by the injected MAb. Our findings indicate that functional inactivation of L-selectin by MEL-14 treatment prevented migration of naive L-selectin ⁺ CTL through high endothelial venules (HEV) and their accumulation in PLN draining the tumor area, thereby precluding the initiation of a tumor-specific CTL response that takes place primarily at this site. © 1996 Wiley-Liss, Inc.     

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy.     

Management of Toxicity Induced by Anti-EGFR Therapy in Metastatic Colorectal Cancer

Use of anti-epidermal growth factor receptor (anti-EGFR) agents has yielded significant advances in the treatment of patients with metastatic colorectal cancer. In fact these drugs, which include the monoclonal antibodies cetuximab and panitumumab, can be delivered both as a single agent and in combination with chemotherapy, achieving better survival and quality of life and in some cases also resectability of metastases. However, these agents can result in the development of toxicities that are usually different from those observed with chemotherapy alone. For the management of these adverse effects, proper knowledge is mandatory. Skin toxicity is the most frequent adverse effect. Other toxicities can be observed, such as hypomagnesemia, gastrointestinal toxicity, and thromboembolic events. Severe infusion reactions can be life-threatening. For these reasons a review of anti-EGFR-drug-related toxicity is useful for clinical practice.     

Myeloid-derived suppressor cell role in tumor-related inflammation

Chronic inflammatory state can create a proper environment for neoplastic onset and sustain cancer growth. The inflammatory state that arises at the tumor edge could contribute to immune escape phenomena in many ways. Myeloid-derived suppressor cells (MDSCs), a cell population that contributes to tumor escape, immune tolerance, and suppression, respond to a variety of pro-inflammatory and anti-inflammatory stimuli, which drive their recruitment and activation. Understanding how the inflammatory milieu favours tumor escape through the accumulation of MDSCs could be very useful to improve the efficacy of cancer immunotherapy.     

Tumor-induced immune dysfunctions caused by myeloid suppressor cells.

In the late 1970s, several findings suggested that accessory cells distinct from lymphocytes might suppress immune reactivity in tumor-bearing hosts. Studies in animal models and patients later confirmed that cells driven to act as dominant immune suppressors by growing cancers could subvert the immune system. These cells have also been termed natural suppressors, a functional definition connoting their ability to hamper various T- and B-lymphocyte responses without prior activation and independently from antigen and MHC restriction. These properties were attributed to distinct cell populations. The phenotypic discrepancies, together with the lack of antigen specificity, have generated serious restraints to research on tumor-induced suppression. Recent evidence indicates that suppressor cells are closely related to immature myeloid precursors and can be found in several situations that can exert adverse effects on the immunotherapy of cancer. The present review is an attempt to address the nature and properties of immature myeloid suppressors and their relationship to dendritic cells and macrophages, with the aim of clarifying the complex network of tumor-induced, negative regulators of the immune system.