Cancer-immune coevolution dictated by antigenic mutation accumulation

Reviewer #1 (Public review):

Summary:

The topic of tumor-immune co-evolution is an important, understudied topic with, as the authors noted, a general dearth of good models in this space. The authors have made important progress on the topic by introducing a stochastic branching process model of antigenicity/immunogenicity and measuring the proportion of simulated tumors that go extinct. The model is extensively explored, and the authors provide some nice theoretical results in addition to simulated results.

Major comments

The text in lines 183-191 is intuitively and nicely explained. However, I am not sure all of it follows from the figure panels in Figure 2. For example, the authors refer to a mutation that has a large immunogenicity, but it's not shown how many mutations, or the relative size of the mutations in Figure 2. The same comment holds true for the claim that spikes also arise for mutations with low antigenicity.

Reviewer #2 (Public review):

Summary:

In this work, the authors developed a model of tumour-immune dynamics, incorporating stochastic antigenic mutation accumulation and escape within the cancer cell population. They then used this model to investigate how tumour-immune interactions influence tumour outcome and summary statistics of sequencing data.

Strengths:

This novel modeling framework addresses an important and timely topic. The authors consider the useful question of how bulk and single-cell sequencing may provide insights into the tumour-immune interactions and selection processes.

Weaknesses:

One set of conclusions presented in the paper is the presence of cyclic dynamics between effector/cancer cells, antigenicity, and immunogenicity. However, these conclusions are supported in the manuscript by two sample trajectories of stochastic simulations, and these provide mixed support for the conclusions (i.e. the phasing asynchrony described in the text does not seem to apply to Figure 2C). Similarly, the authors also find immune selection effects on the shape of the mutational burden in Figure 5 D/H using a qualitative comparison between the distributions and theoretical predictions in the absence of immune response. However the discrepancy appears quite small in panel D, and there are no quantitative comparisons provided to evaluate the significance. An analysis of the robustness of all the conclusions to parameter variation is missing. Lastly, the role of the Appendix results in the main messages of the paper is unclear.