The impressive success of cancer immune therapy reached its limitations and failed in its efficacy with immune
deserted KRAS mutated tumors that constitute 45% of colorectal cancers. These patients have fewer
treatment options necessitating the development of effective alternate therapy. Of late reovirus, with a double-
stranded RNA genome, showed therapeutic efficacy in an oncogenic KRAS transformed colorectal tumors.
Although previously studied for its oncolytic properties reovirus is being increasingly appreciated for its immune
stimulation properties. However, its participation in immune stimulation, precisely utilizing two intimately related
immune and autophagic modulatory pathways, remains largely unexplored. Preliminary results indicate that
reovirus preferentially exploits the immune deserted mutant KRAS tumor microenvironment to successfully
support its propagation in conjunction with destruction of the tumor cells. Furthermore, reovirus induces
autophagy in KRAS mutated microenvironment. Knowledge gaps: It is crucial to understand the mechanism
adopted by reovirus to facilitate the immune enrichment of mutant KRAS driven immune deserted
microenvironment in colorectal cancer. The contribution of autophagic pathway in accentuating the process is
unclear. Understanding the control mechanism between the autophagy and immune pathways is critical.
Project hypothesis: The dual mode of action exerted by reovirus can be successfully translated to the clinic by
augmenting the induction of the autophagy pathway. We propose to study the pattern of reovirus mediated
induction of the autophagic machinery and determine how the molecular event is translated in improving the
immune stimulation characteristics in KRAS mutated colorectal Cancer. In this context we will make use of
KRAS mutant and wildtype colorectal cancer cell lines and our newly developed KPC:APC (tamoxifen-
inducible KRAS-mutated colorectal cancer) mouse models along with the well-established syngeneic mouse
model of colorectal cancer to mechanistically explore the process of crosstalk between the two pathways.
Results will improve the understanding of the dynamics of KRAS mutated immune deserted cold tumors in
facilitating reovirus to act as an immune stimulator Impact: This project will have dual impact of providing an
enriched biomedical science related research environment to the aspiring undergraduate students as well as to
directly address the clinical gap faced by the KRAS mutated colorectal cancer patients. Understanding the
mechanism of cross talk between the autophagy and immune pathways followed by research supported
recommendation of therapeutic induction of autophagy to improve immune therapy responsiveness of KRAS
mutated colorectal cancer will be of paradigm clinical implications. In this pursuit we will AIM1: Demonstrate
crosstalk between autophagy and immune pathways in reovirus treated KRAS mutant and wildtype colorectal
cancer cell lines. AIM2: Examine if autophagy induction promotes reovirus mediated immune stimulation in
KRAS mutated cold colorectal tumors in transgenic and syngeneic mouse models.