Abstract 1140: A new twist on an old strategy: Can the lymph node environment help cancers escape immune surveillance

Cancer cells are selected for strategies to proliferate, invade, and metastasize within an organism. One such strategy is an ability to create an acidic microenvironment. This acidity stems from an increase in H+ production associated with elevated glucose metabolism. This, combined with poor perfusion, results in an acidic extracellular pH (pHe) of 6.5 - 6.9 in malignant tumors. The resulting acidic environment is toxic to normal cells, giving tumor cells an adaptive advantage. Further, it inhibits immune surveillance, although the mechanism by which this occurs is not entirely clear. However, it is well known that an acidic pH profoundly inhibits T cell effector function with minimal effect on T cell viability. Lymph nodes are the primary site for naive T cell activation yet are the most common site of metastasis. Reversible suppression of T cell effector function naturally occurs within the lymph node, creating a site of immune privilege. As a result of these findings we hypothesized that cancer cells exploit this normal physiological function, which may be occurring in the lymph nodes. While lymph nodes are known to be hypoxic, nothing to date is known regarding their pH. Here, we show using four different approaches that the pH of lymph nodes is acidic. All experiments were performed using a murine model under normal, inflammatory and tumor bearing conditions. We interrogated lymph node pH using microelectrodes, chemical exchange saturation transfer (CEST) MRI, imaging with pH-low inserting peptide, pHLIP, and intravital imaging (IVI) of pH sensitive fluorescent dyes; all of which reported an acidic pH between 6.2-6.8. With the aid of a novel lymph node window chamber technique we were able to both image and measure the in vivo pH of a murine lymph node. This novel technique granted us the unique opportunity to acquire enough data to accurately map the pH of the lymph node. These IVI images together with pHLIP immunostaining showed that this acidity was restricted to subcortical regions known to contain antigen presenting dendritic cells and lymphocytes. Because this acidity was so extreme and was not affected by NaHCO3, we hypothesize that its maintenance must be an active process. Collective these data demonstrate that murine lymph nodes sustain an acidic pH under altering physiologic conditions. We hypothesize that cancer cells may be adopting the normal physiological conditions found in the lymph nodes to escape immune surveillance. Citation Format: Veronica Estrella, Pawel Swietach, Kim Luddy, Dominique Abrahams, Pedro Enriquez-Navas, Yana Reshetnyak, Mehdi Damaghi, Robert J. Gillies. A new twist on an old strategy: Can the lymph node environment help cancers escape immune surveillance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1140.