Protein handling, modification and folding in the endoplasmic reticulum (ER) are tightly regulated processes that determine cell function, fate and survival. In several tumour types, diverse ...oncogenic, transcriptional and metabolic abnormalities cooperate to generate hostile microenvironments that disrupt ER homeostasis in malignant and stromal cells, as well as infiltrating leukocytes. These changes provoke a state of persistent ER stress that has been demonstrated to govern multiple pro-tumoural attributes in the cancer cell while dynamically reprogramming the function of innate and adaptive immune cells. Aberrant activation of ER stress sensors and their downstream signalling pathways have therefore emerged as key regulators of tumour growth and metastasis as well as response to chemotherapy, targeted therapies and immunotherapy. In this Review, we discuss the physiological inducers of ER stress in the tumour milieu, the interplay between oncogenic signalling and ER stress response pathways in the cancer cell and the profound immunomodulatory effects of sustained ER stress responses in tumours.
An innovative nanodrug‐delivering‐drug strategy , utilizing β‐Elemene and stanene nanosheets (β‐Elemene@Stanene), has been developed to in situ engineer tumor‐associated macrophages and bolster ...cancer chemo‐immunotherapy. This study provides insights into the immunomodulatory capability of β‐Elemene@Stanene and highlights the nanodrug‐delivering‐drug strategy for the treatment of immunosuppressive tumors, as reported by Wei Tao, Tian Xie et al. in their Research Article (e202308413).
Immune modulation in the next decade PLEYER, U
Acta ophthalmologica (Oxford, England),
September 2011, 2011-09-00, 20110901, Volume:
89, Issue:
s248
Journal Article
Antibody responses during infection and vaccination typically undergo affinity maturation to achieve high-affinity binding for efficient neutralization of pathogens
. Similarly, high affinity is ...routinely the goal for therapeutic antibody generation. However, in contrast to naturally occurring or direct-targeting therapeutic antibodies, immunomodulatory antibodies, which are designed to modulate receptor signalling, have not been widely examined for their affinity-function relationship. Here we examine three separate immunologically important receptors spanning two receptor superfamilies: CD40, 4-1BB and PD-1. We show that low rather than high affinity delivers greater activity through increased clustering. This approach delivered higher immune cell activation, in vivo T cell expansion and antitumour activity in the case of CD40. Moreover, an inert anti-4-1BB monoclonal antibody was transformed into an agonist. Low-affinity variants of the clinically important antagonistic anti-PD-1 monoclonal antibody nivolumab also mediated more potent signalling and affected T cell activation. These findings reveal a new paradigm for augmenting agonism across diverse receptor families and shed light on the mechanism of antibody-mediated receptor signalling. Such affinity engineering offers a rational, efficient and highly tuneable solution to deliver antibody-mediated receptor activity across a range of potencies suitable for translation to the treatment of human disease.
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