Abstract B51: Tumor cell evolutionary strategies to overcome immune response
Authors: Luddy Kimberly A. , Poleszczuk Jan , Hashim Arig Ibrahim , Damaghi Mehdi , Gillies Robert , Brown Joel , Gatenby Robert 
Published: March 2017

Abstract
Introduction: The human immune system is complex, dynamic, and highly effective with system tools ranging from simplistic barrier formation to innate and adaptive cellular responses. In turn, the organisms subject to the immune response can evolve a number of different adaptive strategies. Here we examine these evolutionary dynamics in host immune response to cancer focusing on available strategies that permit cancer cells to evade the immune response.
Materials and Methods: Two rapidly proliferating human cell lines, SW620 colon cancer and MDA-MB-231 triple negative breast cancers were subjected to repeated exposure to either immune conditioned media created by lipopolysaccharide stimulated immune cells or intermittent direct culturing with human peripheral blood leucocytes. Resulting phenotypes were evaluated for alterations in growth dynamics, immune resistance, and gene expression.
Results: Conditioned media had only slight effects on tumor cell death. However, after 4 months selected cells have an increased resistance to T cell mediated killing. Co-culturing with immune cells at high effector to target ratios resulted in strong selection with greater than 50% tumor cell death. After 15 rounds we evolved cancer cells that were resistant to this killing. Interestingly, In-vitro selection of SW620, a more rapidly proliferating cell line, resulted in an anti-apoptotic strategy when confronted with immune cells while MDA-MB-231 cells increased fecundity.
Conclusion: Utilizing different arms of the immune system resulted in different styles and strengths of selection force. Additionally, we demonstrate that the two different cell lines employed distinctly different strategies to overcome host immune response. The MDA-MB-231 population adapts to immune attack by accelerating proliferation so that it exceeds the death rate imposed by the immune system. Interestingly, this has been observed clinically as some tumors show explosive growth during immunotherapy. In contrast, the SW620 cells upregulate anti-apoptotic cellular machinery which appears to be phenotypically costly so that proliferation of resistant cells is significantly diminished. As clinical applications of immunotherapy continue to grow it is imperative that we do not ignore the evolutionary consequences of immune selection on the tumor phenotype. While investigations of immune evasive strategies in tumor cells has led to a growing list of specific mechanisms, here we look to not only expand this list but to exploit it. Detailed understanding of the specific adaptive strategy for each tumor population may reveal phenotypic vulnerabilities to second line treatments.
Citation Format: Kimberly A. Luddy, Jan Poleszczuk, Arig Ibrahim Hashim, Mehdi Damaghi, Robert Gillies, Joel Brown, Robert Gatenby. Tumor cell evolutionary strategies to overcome immune response. [abstract]. In: Proceedings of the AACR Special Conference on Engineering and Physical Sciences in Oncology; 2016 Jun 25-28; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2017;77(2 Suppl):Abstract nr B51.