Tolerance Needed: It's a common enough occurrence: You're sick as a dog with a cold, but the person in the office next door just has a few sniffles. What accounts for this difference? Most commonly, these sorts of differences are chalked up to differences in resistance—perhaps you have higher viral loads than your office mate. But such differences can also involve differences in the ability to tolerate the same amount of virus. Deciphering the contribution of resistance versus tolerance, however, is difficult. Jamieson et al. (p. 1230 , published online 25 April) studied a mouse model of viral and bacterial co-infection where tolerance and resistance could be separated. Mice infected with influenza virus were more likely to succumb to a secondary infection with Legionella pneumophila as a result of impaired tolerance to tissue damage, rather than because of a difference in bacterial burden.

Tuberculosis causes 2 million deaths per year, yet in most cases the immune response successfully contains the infection and prevents disease outbreak. Induced lymphoid structures associated with pulmonary granuloma are observed during tuberculosis in both humans and mice and could orchestrate host defense. To investigate whether granuloma perform lymphoid functions, mice lacking secondary lymphoid organs (SLO) were infected with Mycobacterium tuberculosis (MTB). As in WT mice, granuloma developed, exponential growth of MTB was controlled, and antigen‐specific T‐cell responses including memory T cells were generated in the absence of SLO. Moreover, adoptively transferred T cells were primed locally in lungs in a granuloma‐dependent manner. T‐cell activation was delayed in the absence of SLO, but resulted in a normal development program including protective subsets and functional recall responses that protected mice against secondary MTB infection. Our data demonstrate that protective immune responses can be generated independently of SLO during MTB infection and implicate local pulmonary T‐cell priming as a mechanism contributing to host defense.

Even though Mycobacterium tuberculosis (Mtb) remains one of the top microbial killers, more than 90% of the 2 billion infected individuals never develop active tuberculosis (TB), indicating efficient immune control of infection in these individuals. Immune mechanisms promoting either control or reactivation of TB are incompletely understood. Kinetic analyses of T‐cell responses against Mtb in C57BL/6 mice revealed surface expression of inducible co‐stimulatory molecule (ICOS) on >30% of all CD4⁺ T cells, suggesting a pivotal role of this costimulatory molecule of the CD28 family in TB control. Surprisingly, Mtb‐infected ICOS^−/− mice showed lower bacterial burden during the late chronic stage of infection as compared to WT controls. ICOS deficiency resulted in a reduced Mtb‐specific CD8⁺ T‐cell response during late‐stage infection. In contrast, the polyclonal CD4⁺ Th1 response against Mtb was increased, most likely caused by diminished numbers and frequencies of Tregs. Thus, by altering effector T‐cell populations differentially, ICOS signaling modulates TB control in the late stage of infection.

The stromal tumor microenvironment (TME) consists of immune cells, vascular and neural structures, cancer-associated fibroblasts (CAFs), as well as extracellular matrix (ECM), and favors immune escape mechanisms promoting the initiation and progression of digestive cancers. Numerous ECM proteins released by stromal and tumor cells are crucial in providing physical rigidity to the TME, though they are also key regulators of the immune response against cancer cells by interacting directly with immune cells or engaging with immune regulatory molecules. Here, we discuss current knowledge of stromal proteins in digestive cancers including pancreatic cancer, colorectal cancer, and gastric cancer, focusing on their functions in inhibiting tumor immunity and enabling drug resistance. Moreover, we will discuss the implication of stromal proteins as therapeutic targets to unleash efficient immunotherapy-based treatments.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a vast stromal reaction that arises mainly from cancer-associated fibroblasts (CAFs) and promotes both immune escape and tumor growth. Here, we used a mouse model with deletion of the activin A receptor ALK4 in the context of the Kras^G12D mutation, which strongly drives collagen deposition that leads to tissue stiffness. By ligand–receptor analysis of single-cell RNA-sequencing data, we identified that, in stiff conditions, neoplastic ductal cells instructed CAFs through sustained platelet-derived growth factor (PDGF) signaling. Tumor-associated tissue rigidity resulted in the emergence of stiffness-induced CAFs (siCAFs) in vitro and in vivo. Similar results were confirmed in human data. siCAFs were able to strongly inhibit CD8⁺ T-cell responses in vitro and in vivo, promoting local immunosuppression. More importantly, targeting PDGF signaling led to diminished siCAF and reduced tumor growth. Our data show for the first time that early paracrine signaling leads to profound changes in tissue mechanics, impacting immune responses and tumor progression. Our study highlights that PDGF ligand neutralization can normalize the tissue architecture independent of the genetic background, indicating that finely tuned stromal therapy may open new therapeutic avenues in pancreatic cancer.